USP7 sustains hematopoietic stem cell homeostasis partially via PU.1 stabilization
Open accessAbstract
Hematopoietic stem cell (HSC) self-renewal and lineage commitment are tightly controlled by post-translational mechanisms, but the contribution of deubiquitination to these processes remains unclear. Here, we define ubiquitin-specific protease 7 (USP7) as a critical regulator of HSC maintenance and hematopoietic homeostasis. Conditional Usp7 deletion in murine HSCs triggered rapid stem cell depletion, multilineage cytopenias, and systemic hematopoietic failure. Usp7-deficient HSCs displayed defective quiescence, reduced competitive repopulation capacity, and aberrant lineage differentiation. Mechanistically, USP7 directly binds and deubiquitinates the transcription factor PU.1, shielding it from proteasomal degradation. Loss of USP7 destabilized PU.1, leading to suppressed expression of PU.1 target genes critical for HSC quiescence and lineage specification. In competitive transplants, USP7-null HSCs exhibited severely impaired self-renewal, marked by diminished engraftment and differentiation. Ectopic PU.1 expression partially restored HSC function, confirming the USP7-PU.1 axis as essential for HSC integrity. Our study identifies USP7 as a post-translational checkpoint in hematopoiesis and reveals a novel deubiquitination-dependent mechanism controlling stem cell fate. These findings highlight the USP7-PU.1 interaction as a potential therapeutic target for hematopoietic disorders.
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Written from the paper’s full text.
TL;DR
Conditional deletion of Usp7 in murine hematopoietic stem cells causes HSC depletion, multilineage cytopenias, impaired quiescence, and defective repopulation. USP7 directly binds and deubiquitinates PU.1, stabilizing it; ectopic PU.1 partially rescues Usp7-deficient HSC repopulation.
Key findings
- Usp7 deletion in HSCs produced rapid stem cell depletion, multilineage cytopenias, and hematopoietic failure; Usp7 mRNA was reduced by >80%, and LT-HSC G0 fraction fell to ~58% in Usp7−/− mice versus 73% in controls.
- Usp7-deficient HSCs showed reduced competitive repopulation and multilineage differentiation, with secondary transplants showing comparable impairment; homing to BM was not significantly impaired, though spleen homing was decreased.
- RNA-seq of sorted LT-HSCs found 128 upregulated and 127 downregulated genes in Usp7-deficient cells; PU.1 mRNA was unchanged but PU.1 protein was substantially decreased, with PU.1 target genes Myc and Gfi1 downregulated and Cdk1 and E2f1 upregulated.
- USP7 directly interacted with PU.1 via its MATH and UBL domains, and USP7WT but not catalytically inactive USP7C223S reduced ubiquitinated PU.1; ectopic PU.1 partially restored donor-derived cell proportions in PB and BM.
Methods
- Conditional Usp7fl/fl mice were crossed with Mx1-Cre or Scl-Cre; deletion was induced with poly(I:C) or tamoxifen in 8–12-week-old C57BL/6 mice.
- Competitive and secondary BM transplantations, cell-autonomous post-transplant deletion, lentiviral PU.1 rescue, flow cytometry, CFU assays, homing assays, apoptosis assays, BrdU incorporation, 5-FU challenge, and complete blood counts were used.
- RNA-seq was performed on sorted LT-HSCs with two biological replicates per group, using DESeq2 with p-adjusted < 0.05 and fold change > 2; mechanistic assays included Co-IP, GST pull-down, deubiquitination assays, western blotting, and qRT-PCR.
Limitations
- The paper states that USP7 likely stabilizes additional key transcription factors beyond PU.1, noting RNA-seq deregulation downstream of IKZF1, EBF1, TCF3, and PAX5, and that PU.1 rescue was partial.
- The paper states unresolved questions about how MATH/UBL domains selectively engage PU.1 amid other substrates, whether stress modulates USP7–PU.1 interactions, and whether PU.1 stabilization affects chromatin occupancy.
- Evident from the text: RNA-seq used only two biological replicates per group; Mx1-Cre can also affect stromal cells, although Scl-Cre was used for some experiments; homing was impaired in spleen but not BM, and apoptosis did not differ significantly between Usp7−/− and control LT-HSCs.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
20 of 26 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The Scl-Cre strain is HSPCs specific.
“tamoxifen-induced HSPCs specific Scl-Cre strain 12”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] Gothert JR Gustin SE Hall MA Green AR Gottgens B Izon DJ In vivo fate-tracing studies using the Scl stem cell enhancer: embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis Blood 2005 105 2724 32 15598809 source
- Premisecitation
In preleukemic states (e.g., MDS), PU.1 downregulation permits clonal expansion.
“In preleukemic states (e.g., MDS), where PU.1 downregulation permits clonal expansion 33-35”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [33] Rosenbauer F Wagner K Kutok JL Iwasaki H Le Beau MM Okuno Y Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1 Nat Genet 2004 36 624 30 15146183 source
- cites [34] Stirewalt DL Fine-tuning PU.1 Nat Genet 2004 36 550 1 15167927 source
- cites [35] Dakic A Metcalf D Di Rago L Mifsud S Wu L Nutt SL PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis J Exp Med 2005 201 1487 502 15867096 PMC2213186 source
The Results and Discussion (page not provided) show that PU.1 loss in mice expanded granulocytic progenitors, and the Discussion describes a related preleukemic mouse model with reduced PU.1 expression. The paper does not establish that PU.1 downregulation permits clonal expansion in MDS; its observed progenitor expansion is not identified as clonal expansion. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
In competitive transplants, USP7-null HSCs exhibit severely impaired self-renewal, marked by diminished engraftment and differentiation.
“In competitive transplants, USP7-null HSCs exhibited severely impaired self-renewal, marked by diminished engraftment and differentiation.”
Quote in the paperSubstantial claim - Findingown data
Ectopic PU.1 expression partially restores HSC function.
“Ectopic PU.1 expression partially restored HSC function, confirming the USP7-PU.1 axis as essential for HSC integrity.”
- Also stated in: § Introduction · plain
“Restoring PU.1 partially rescues Usp7-deficient HSC defects”
Quote in the paperSubstantial claim- Rests on an assumption: PU.1 is a transcription factor essential for myeloid/lymphoid priming.
- Also stated in: § Introduction · plain
- Findingown data
Usp7 deficiency decreases BM frequencies of Mac-1+Gr-1+ myeloid cells.
“a significant decrease was observed in the BM frequencies of both Mac-1+Gr-1+ myeloid cells and CD41+ megakaryocytes, while the frequencies of erythroid cells were markedly increased”
Quote in the paperSubstantial claim
- Findingown data
USP7 is relatively highly expressed in HSCs in the normal human hematopoietic system.
“USP7 was relatively highly expressed in HSCs”
Quote in the paperNot a substantial claim - Findingown data
In Usp7-/- mice at 4 weeks after the last poly(I:C) injection, both the frequencies and absolute numbers of LSK (Lin-Sca-1+c-Kit+) cells, encompassing LT-HSCs, ST-HSCs, and MPPs, were significantly reduced relative to Usp7+/+ mice.
“However, both the frequencies and absolute numbers of LSK (Lin-Sca-1+c-Kit+) cells—encompassing LT-HSCs, ST-HSCs, and MPPs—were significantly reduced in Usp7-/- mice relative to Usp7+/+ mice at 4 weeks post the last poly (I:C) injection (Fig. 2B-E).”
Quote in the paperSubstantial claim - Findingown data
Usp7 deficiency elevates CD3+ T cell frequencies in peripheral blood.
“Usp7 deficiency led to a notable reduction in the frequencies of B220+ B cells and an elevation in the frequencies of CD3+ T cells in PB”
Quote in the paperNot a substantial claim - Findingown data
qRT-PCR on sorted HSCs confirmed the significant downregulation of key pathway genes, including Flt3, Gata1, and c-Kit.
“we performed qRT-PCR on sorted HSCs and confirmed the significant downregulation of key pathway genes, including Flt3, Gata1, and c-Kit (Supplementary Fig. 8).”
Quote in the paperNot a substantial claim - Findingown data
A marked decrease in Usp7-/- donors was noted within the spleens at 18 h after transplant.
“however, a marked decrease in Usp7-/- donors was noted within the spleens (Supplementary Fig. 6E)”
Quote in the paperSubstantial claim - Findingown data
Repopulation by Usp7-/- BM cells was significantly reduced relative to Usp7+/+ cells at 4, 8, 12, and 16 weeks after transplant.
“Our results showed that repopulation by Usp7-/- BM cells was significantly reduced relative to Usp7+/+ cells at indicated times after transplant (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Usp7-deficient HSPCs, comprising LT-HSCs, ST-HSCs, MPPs, GMPs, MEPs and CMPs, exhibited a dramatic reduction.
“Usp7-deficient HSPCs, comprising LT-HSCs, ST-HSCs, MPPs, GMPs, MEPs and CMPs, also exhibited a dramatic reduction (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
Usp7 deficiency reduces white blood cell counts in mice.
“complete blood count analyses demonstrated a marked reduction in white blood cell counts and platelet counts in Usp7-/- mice compared with Usp7+/+ mice”
Quote in the paperSubstantial claim - Findingown data
Frequencies of LSK and LT-HSCs in the spleens of Usp7-/- mice remained unchanged compared to controls.
“the frequencies of LSK and LT-HSCs remain unchanged.”
Quote in the paperNot a substantial claim - Findingown data
No significant differences were observed between Usp7+/+ and Usp7-/- donors in homing to BM at 18 h after transplant.
“No significant differences were observed between the Usp7+/+ and Usp7-/- donors in the BM at 18 h after transplant”
Quote in the paperSubstantial claim - Findingown data
At 2 weeks after a single injection of 5-FU, the recovery rate of neutrophils in Scl-Cre; Usp7fl/fl mice was significantly slower compared to control mice.
“5-FU killing assay indicated that at 2 weeks after a single injection of 5-FU, the recovery rate of neutrophils in Scl-Cre; Usp7fl/fl mice was significantly slower compared to the control mice (Supplementary Fig. 7A-C).”
Quote in the paperSubstantial claim - Findingown data
Usp7 deficiency reduces B220+ B cell frequencies in peripheral blood.
“Usp7 deficiency led to a notable reduction in the frequencies of B220+ B cells and an elevation in the frequencies of CD3+ T cells in PB”
Quote in the paperSubstantial claim - Findingown data
No significant difference in apoptosis was detected between Usp7-/- and Usp7+/+ LT-HSCs.
“Conversely, no significant difference in apoptosis was detected between Usp7-/- and Usp7+/+ LT-HSCs (Supplementary Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
RNA-seq analysis on sorted BM LT-HSCs from Usp7+/+ and Usp7-/- mice revealed 128 upregulated and 127 downregulated genes in Usp7-deficient LT-HSCs.
“The analysis revealed 128 upregulated and 127 downregulated genes in Usp7-deficient LT-HSCs (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
GSEA results revealed a significant down-regulation trend in gene sets related to hematopoietic cell lineage, the G2/M checkpoint of the cell cycle, and apoptosis in the HSCs of Usp7-/- mice.
“Additionally, GSEA results revealed a significant down-regulation trend in gene sets related to hematopoietic cell lineage, the G2/M checkpoint of the cell cycle, and apoptosis in the HSCs of Usp7-/- mice (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
Approximately 58% of LT-HSCs were in G0 in Usp7-/- mice compared with 73% in Usp7+/+ mice.
“approximately 58% of LT-HSCs were in G0 in Usp7-/- mice compared with 73% in Usp7+/+ mice (Fig. 2H).”
Quote in the paperSubstantial claim - Findingown data
PU.1 protein is downregulated in Usp7-deficient total BM cells.
“The downregulation of PU.1 protein in Usp7-deficient LK cells (Fig. 5G) and Usp7-deficient total BM cells (Fig. 6A) supports this notion.”
Quote in the paperSubstantial claim - Findingown data
Purified USP7 markedly reduced the ubiquitination of PU.1 in an in vitro deubiquitination assay.
“As illustrated in Fig. 6K, the purified USP7 markedly reduced the ubiquitination of PU.1.”
Quote in the paperSubstantial claim - Findingown data
Following transplantation into secondary recipients, a comparable repopulation trend was observed.
“Following transplantation into secondary recipients, the results exhibited a comparable repopulation trend (Supplementary Fig. 6A-D)”
Quote in the paperSubstantial claim - Findingown data
Usp7 depletion reduces B cell frequencies in spleens.
“Usp7 depletion did not trigger significant alterations in the frequencies of differentiated lineages except a reduction in B cells in spleens”
Quote in the paperNot a substantial claim - Findingown data
Usp7 deficiency reduces platelet counts in mice.
“complete blood count analyses demonstrated a marked reduction in white blood cell counts and platelet counts in Usp7-/- mice compared with Usp7+/+ mice”
Quote in the paperSubstantial claim - Findingown data
The C-terminal DBD domain of PU.1 did not interact with USP7.
“The results demonstrate that the C-terminal DBD domain of PU.1 did not interact with USP7 (Fig. 6G).”
Quote in the paperNot a substantial claim - Findingown data
Usp7 deficiency decreases BM frequencies of CD41+ megakaryocytes.
“a significant decrease was observed in the BM frequencies of both Mac-1+Gr-1+ myeloid cells and CD41+ megakaryocytes, while the frequencies of erythroid cells were markedly increased”
Quote in the paperSubstantial claim - Findingown data
In vivo BrdU incorporation labeling showed a relatively higher proliferation rate of Usp7-/- LT-HSCs.
“In vivo BrdU incorporation labeling also showed the relatively higher proliferation rate of Usp7-/- LT-HSCs (Fig. 2I).”
Quote in the paperSubstantial claim - Findingown data
Heatmaps from KEGG database focusing on the top 3 most significantly enriched pathways revealed that genes associated with metabolic pathways, pathways in cancer, and hematopoietic cell lineage were up-regulated or down-regulated to varying degree.
“The heatmaps results created from KEGG database focusing on the top 3 most significantly enriched pathways revealed that genes associated with metabolic pathways, pathways in cancer, and hematopoietic cell lineage were up-regulated or down-regulated to varying degree (Fig. 5C).”
Quote in the paperNot a substantial claim - Findingown data
Knockdown of USP7 using specific shRNAs in HEK293T cells increased PU.1 ubiquitination under the same experimental settings.
“Conversely, knockdown of USP7 using specific shRNAs in HEK293T cells increased PU.1 ubiquitination under the same experimental settings (Fig. 6I).”
Quote in the paperSubstantial claim - Findingown data
Ectopic expression of PU.1 partially restored the repopulation capacity of Usp7-deficient HSPCs, as demonstrated by elevated donor-derived cell proportions in both PB and BM compared to controls.
“Our results indicate that ectopic expression of PU.1 partially restored the repopulation capacity of Usp7-deficient HSPCs, as demonstrated by elevated donor-derived cell proportions in both PB and BM compared to controls (Fig. 7C-D).”
Quote in the paperSubstantial claim - Findingown data
Total colony numbers of Usp7-/- BM cells, particularly megakaryocyte progenitor cells (CFU-M colonies), were significantly decreased.
“Meanwhile, the total colony numbers of Usp7-/- BM cells, particularly megakaryocyte progenitor cells (CFU-M colonies), were significantly decreased (Supplementary Fig. 5A-B).”
Quote in the paperSubstantial claim - Findingown data
Total spleen cellularity of Usp7-/- mice was significantly lower than controls.
“although the total spleen cellularity of Usp7-/- mice was significantly lower compared to the controls”
Quote in the paperNot a substantial claim - Findingown data
A profound reduction in donor contribution to T cells, B cells, and myeloid cells was observed in recipients of Usp7-/- BM cells.
“Of note, a profound reduction in donor contribution to T cells (Fig. 3C), B cells (Fig. 3D), and myeloid cells (Fig. 3E) was observed in recipients of Usp7-/- BM cells”
Quote in the paperSubstantial claim - Findingown data
Usp7 deletion reduced the frequencies of LK (Lin-Sca-1-c-Kit+) progenitor populations, including CMPs, GMPs, MEPs, and CLPs.
“Moreover, Usp7 deletion also led to the reduced frequencies of LK (Lin-Sca-1-c-Kit+) progenitor populations, including CMPs, GMPs, MEPs, and CLPs (Fig. 2F-G).”
Quote in the paperSubstantial claim - Findingown data
In competitive BM transplantations where Usp7 deletion was triggered after transplant, there was a dramatic reduction in donor engraftment in PB and BM by Usp7-deficient BM cells.
“We found a dramatic reduction in donor engraftment in PB and BM by Usp7-deficient BM cells (Fig. 4B-C).”
Quote in the paperSubstantial claim - Findingown data
Compared to Usp7+/+ HSCs, the mRNA level of PU.1 in Usp7-/- HSCs remained unchanged.
“compared to the Usp7+/+ HSCs, the mRNA level of PU.1 in Usp7-/- HSCs remained unchanged”
Quote in the paperSubstantial claim - Findingown data
An interaction between endogenous USP7 and PU.1 was detectable in 32D cells, a mouse myeloid progenitor cell line.
“Furthermore, an interaction between endogenous USP7 and PU.1 was also detectable in 32D cells, a mouse myeloid progenitor cell line (Fig. 6C).”
Quote in the paperSubstantial claim - Findingown data
Despite the unaltered mRNA level, the protein abundance of PU.1 was substantially decreased in sorted Usp7-/- LK cells.
“However, despite the unaltered mRNA level, the protein abundance of PU.1 was substantially decreased in sorted Usp7-/- LK cells (Fig. 5G)”
Quote in the paperSubstantial claim - Findingown data
Usp7 deletion did not change overall bone marrow cellularity.
“The overall BM cellularity remained largely unchanged following Usp7 deletion (Fig. 2A).”
Quote in the paperNot a substantial claim - Findingown data
PU.1 (also known as SPI1) was consistently identified as one of the most abundant transcription factors regulated by USP7.
“We noticed that PU.1 (also known as SPI1), which is a determinant factor for myeloid differentiation and plays a crucial regulatory role in hematopoietic development 17, 18, was consistently identified as one of the most abundant transcription factors regulated by USP7.”
Quote in the paperSubstantial claim - Findingown data
USP7 and PU.1 reciprocally co-immunoprecipitated.
“The results showed that USP7 and PU.1 reciprocally co-immunoprecipitated (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
The reductions in white blood cell and platelet counts persist for 2 to 4 weeks following final poly(I:C) injection.
“a phenomenon that persisted for 2 to 4 weeks following the final poly(I:C) injection”
Quote in the paperNot a substantial claim - Findingown data
The expression pattern of USP7 in mice is conserved in humans, with USP7 expressed in human CD34+ HSCs and early lineage-committed progenitor cells at the single-cell level.
“the expression pattern of USP7 in mice was conserved in humans, with USP7 expressed in human CD34+ HSCs and early lineage-committed progenitor cells at the single-cell level”
Quote in the paperNot a substantial claim - Findingown data
Co-expression of USP7WT, but not USP7C223S, substantially reduced the levels of ubiquitinated-PU.1.
“Co-expression of USP7WT, but not USP7C223S, substantially reduced the levels of ubiquitinated-PU.1 (Fig. 6H).”
Quote in the paperSubstantial claim - Findingown data
Metascape analysis showed that the top 3 most significantly enriched pathways are linked to adaptive immune response, leukocyte differentiation and hematopoietic cell lineage.
“Metascape analysis showed that the top 3 most significantly enriched pathways are linked to adaptive immune response, leukocyte differentiation and hematopoietic cell lineage (Fig. 5B).”
Quote in the paperNot a substantial claim - Findingown data
Comparable hematological results are observed in the Scl-Cre; Usp7fl/fl mouse model.
“Comparable results were also observed in Scl-Cre; Usp7fl/fl mouse model”
Quote in the paperNot a substantial claim - Findingown data
Usp7 depletion does not trigger significant alterations in frequencies of differentiated lineages in spleens.
“Usp7 depletion did not trigger significant alterations in the frequencies of differentiated lineages except a reduction in B cells in spleens”
Quote in the paperNot a substantial claim - Findingown data
Similar reductions in HSPC frequencies were observed in the Scl-Cre; Usp7fl/fl mouse model.
“Consistently, we observed similar results in Scl-Cre; Usp7fl/fl mouse model (Supplementary Fig. 3A-D).”
Quote in the paperNot a substantial claim - Findingown data
USP7 overexpression in HEK293T cells substantially suppressed the CHX-induced degradation of PU.1 protein.
“Moreover, USP7 overexpression in HEK293T cells substantially suppressed the CHX-induced degradation of PU.1 protein (Fig. 6E).”
Quote in the paperSubstantial claim - Findingown data
Sequential 5-FU challenge assay revealed that Scl-Cre; Usp7fl/fl mice died dramatically earlier than Usp7fl/fl mice.
“Sequential 5-FU challenge assay revealed that Scl-Cre; Usp7fl/fl mice died dramatically earlier than Usp7fl/fl mice (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
Usp7-/- HSPCs, comprising LT-HSCs, ST-HSCs, MPPs, GMPs, MEPs and CMPs, displayed a substantial decrease at 16 weeks post-transplantation.
“Usp7-/- HSPCs, comprising LT-HSCs, ST-HSCs, MPPs, GMPs, MEPs and CMPs, also displayed a substantial decrease at 16 weeks post-transplantation (Fig. 3F-G).”
Quote in the paperSubstantial claim - Findingown data
Usp7 deficiency increases BM frequencies of erythroid cells.
“a significant decrease was observed in the BM frequencies of both Mac-1+Gr-1+ myeloid cells and CD41+ megakaryocytes, while the frequencies of erythroid cells were markedly increased”
Quote in the paperSubstantial claim - Findingown data
Frequencies of homed CFSE+ cells within the LSK compartment, LT-HSCs, ST-HSCs, and MPPs were comparable between control and Scl-Cre; Usp7fl/fl mice in the BM.
“the frequencies of homed CFSE+ cells within the LSK compartment, as well as LT-HSCs, ST-HSCs, and MPPs, were comparable between control and Scl-Cre; Usp7fl/fl mice in the BM (Supplementary Fig. 6F-G).”
Quote in the paperSubstantial claim - Interpretationown data
The USP7-PU.1 axis is essential for HSC integrity.
“confirming the USP7-PU.1 axis as essential for HSC integrity”
Quote in the paperSubstantial claim- Rests on an assumption: PU.1 is a transcription factor essential for myeloid/lymphoid priming.
- Interpretationown data
USP7 is a post-translational checkpoint in hematopoiesis.
“Our study identifies USP7 as a post-translational checkpoint in hematopoiesis”
Quote in the paperSubstantial claim- Rests on an assumption: The contribution of deubiquitination to HSC self-renewal and lineage commitment remains unclear.
- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
- Rests on an assumption: HSC self-renewal and lineage commitment are tightly controlled by post-translational mechanisms.
- Interpretationown data
A novel deubiquitination-dependent mechanism controls stem cell fate.
“reveals a novel deubiquitination-dependent mechanism controlling stem cell fate”
Quote in the paperSubstantial claim- Rests on an assumption: The contribution of deubiquitination to HSC self-renewal and lineage commitment remains unclear.
- Rests on an assumption: HSC self-renewal and lineage commitment are tightly controlled by post-translational mechanisms.
- Interpretationown data
PU.1 is an important downstream mediator of USP7.
“identifying PU.1 as an important downstream mediator of USP7”
Quote in the paperSubstantial claim- Rests on an assumption: PU.1 is a transcription factor essential for myeloid/lymphoid priming.
- Interpretationreasoning
The platelet phenotype indicates USP7 may play a regulatory role in HSCs.
“This platelet phenotype indicates that USP7 may play a regulatory role in HSCs.”
Quote in the paperSubstantial claim- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
- Study design and conductown data
Usp7 deletion in Scl-Cre; Usp7fl/fl mice is verified at 1 week after last tamoxifen.
“the deletion of Usp7 in Scl-Cre; Usp7fl/fl mice was similarly verified at 1 week after the last dose of tamoxifen”
Quote in the paperSubstantial claim - Interpretationreasoning
Deubiquitination is a novel regulatory mechanism governing PU.1-dependent transcriptional programs in HSCs.
“These results establish deubiquitination as a novel regulatory mechanism governing PU.1-dependent transcriptional programs in HSCs.”
Quote in the paperSubstantial claim - Interpretationown data
USP7 deficiency does not impair the intrinsic homing capacity of HSCs to the BM.
“This combined evidence demonstrates that USP7 deficiency does not impair the intrinsic homing capacity of HSCs to the BM.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 contributes, at least partially, to the function of USP7 in HSCs.
“These data indicate that PU.1 contributes, as least partially, to the function of USP7 in HSCs.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 is a bona fide substrate of USP7.
“Taken together, these results indicate that PU.1 is a bona fide substrate of USP7.”
Quote in the paperSubstantial claim - Interpretationown data
USP7 directly interacts with PU.1.
“These results indicate that USP7 directly interacts with PU.1.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 may contribute to USP7 knockout caused alteration in normal hematopoiesis.
“Therefore, these data demonstrate that PU.1 may contribute to USP7 knockout caused alteration in normal hematopoiesis.”
Quote in the paperSubstantial claim - Interpretationown data
PU.1 is a novel key target of USP7-mediated regulation in HSCs.
“Mechanistically, we identified the transcription factor PU.1 as a novel key target of USP7-mediated regulation in HSCs.”
Quote in the paperSubstantial claim - Interpretationown data
Usp7 deletion results in impaired self-renewal capacity of HSCs.
“indicating that Usp7 deletion results in impaired self-renewal capacity of HSCs.”
Quote in the paperSubstantial claim - Premisecitation
Mx1 promoter-driving Cre is expressed in both hematopoietic cells and stromal cells.
“Considering that the Mx1 promoter-driving Cre is expressed in both hematopoietic cells and stromal cells 11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Gudmundsson KO Gene Inactivation in Adult Long-Term Hematopoietic Stem Cells Using Inducible Mouse Models Methods Mol Biol 2021 2224 183 93 33606215 source
- Interpretationown data
The reduced long-term repopulation potential of Usp7-deficient HSCs is not due to impaired homing.
“In summary, these data indicate that the reduced long-term repopulation potential of Usp7-deficient HSCs is not due to impaired homing.”
Quote in the paperSubstantial claim - Interpretationown data
USP7 may play an important role in hematopoiesis.
“These data suggest that USP7 may play an important role in hematopoiesis.”
Quote in the paperSubstantial claim- Rests on an assumption: HSC self-renewal and lineage commitment are tightly controlled by post-translational mechanisms.
- Interpretationown data
Usp7 deletion exerts a pronounced effect on normal hematopoiesis.
“Overall, these findings demonstrate that Usp7 deletion exerts a pronounced effect on normal hematopoiesis”
Quote in the paperSubstantial claim- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
- Interpretationreasoning
The observed defects are primarily attributable to PU.1 destabilization.
“These results implicate that the observed defects are primarily attributable to PU.1 destabilization.”
Quote in the paperSubstantial claim - Interpretationreasoning
USP7 acts as a rheostat for HSC fate decisions by coupling protein stabilization to transcriptional control of quiescence.
“In summary, USP7 acts as a rheostat for HSC fate decisions by coupling protein stabilization to transcriptional control of quiescence.”
Quote in the paperSubstantial claim - Interpretationown data
USP7's regulatory network extends far beyond PU.1.
“However, USP7's regulatory network extends far beyond this single transcription factor.”
Quote in the paperNot a substantial claim - Interpretationown data
USP7 inhibitors risk inducing HSC exhaustion, as evidenced by our transplantation assays.
“Conversely, USP7 inhibitors—though promising for cancer—risk inducing HSC exhaustion, as evidenced by our transplantation assays.”
Quote in the paperSubstantial claim - Interpretationreasoning
Substrate selectivity likely explains why USP7 deletion produces more severe hematopoietic defects than PU.1 deficiency alone.
“This substrate selectivity likely explains why USP7 deletion produces more severe hematopoietic defects than PU.1 deficiency alone, as observed in our study.”
Quote in the paperSubstantial claim - Interpretationown data
The partial rescue assay of Usp7-/- HSC defects by PU.1 overexpression further underscores PU.1's pivotal role.
“The partial rescue assay of Usp7-/- HSCs defects by PU.1 overexpression further underscores PU.1's pivotal role.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 9
- May combine two claims. 29
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUSP7 substrates p53 and PTEN regulate stem cell quiescence.
“USP7 substrates (e.g. p53 8, PTEN 9) regulate stem cell quiescence”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [8] Liu Y Elf SE Miyata Y Sashida G Liu Y Huang G p53 regulates hematopoietic stem cell quiescence Cell Stem Cell 2009 4 37 48 19128791 PMC2839936 source
- cites [9] Wu Y Zhu H Wu H PTEN in Regulating Hematopoiesis and Leukemogenesis Cold Spring Harb Perspect Med 2020 10 PMC7528863 31712222 source
The “PTEN Controls HSC Self-Renewal” section reports that PTEN loss drives quiescent long-term hematopoietic stem cells into the cell cycle, supporting PTEN’s role in stem-cell quiescence. The passages found do not establish the sentence’s additional characterization of PTEN as a USP7 substrate; the separate p53 citation is not assessed here. No page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationUSP7 stabilizes hematopoietic transcription factors GATA1, NOTCH1, and IKZF1.
“stabilizes hematopoietic transcription factors like GATA1 5, NOTCH1 6, and IKZF1 7”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [5] Liang L Peng Y Zhang J Zhang Y Roy M Han X Deubiquitylase USP7 regulates human terminal erythroid differentiation by stabilizing GATA1 Haematologica 2019 104 2178 87 30872372 PMC6821630 source
- cites [6] Shan H Li X Xiao X Dai Y Huang J Song J USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia Signal Transduct Target Ther 2018 3 29 30370059 PMC6202415 source
- cites [7] Liu M Zhang Y Wu Y Jin J Cao Y Fang Z IKZF1 selectively enhances homologous recombination repair by interacting with CtIP and USP7 in multiple myeloma Int J Biol Sci 2022 18 2515 26 35414773 PMC8990476 source
May combine two claims.
PremisecitationPU.1 maintains HSC quiescence during inflammatory stress by limiting protein production and suppressing cell cycle progression, thus preventing excessive HSC proliferation.
“PU.1 maintains HSC quiescence during inflammatory stress by limiting protein production and suppressing cell cycle progression, thus preventing excessive HSC proliferation 20.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Chavez JS Rabe JL Loeffler D Higa KC Hernandez G Mills TS PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress J Exp Med 2021 218 e20201169 33857288 PMC8056754 source
Classified as probably not a substantial claim.
PremisecitationHematopoietic-specific deletion of Pu.1 leads to the absolute loss of CMPs and CLPs.
“hematopoietic-specific deletion of Pu.1 leads to the absolute loss of CMPs and CLPs”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Iwasaki H Somoza C Shigematsu H Duprez EA Iwasaki-Arai J Mizuno S Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation Blood 2005 106 1590 600 15914556 PMC1895212 source
The Results (Table 1; page not available) show that CLPs fell below the detection threshold after conditional PU.1 deletion, but CMPs remained measurable at 2 and 4 weeks. The Results also report that both populations began to recover by 6 weeks. Thus, the claim's “absolute loss” overstates the CMP finding and omits the time course. (LLM, conf=0.92)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPlatelets can be produced directly from HSCs.
“Recent studies have suggested that platelets can be produced directly from HSCs 13.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Garyn CM Bover O Murray JW Ma J Salas-Briceno K Ross SR G2 arrest primes hematopoietic stem cells for megakaryopoiesis Cell Rep 2024 43 114388 38935497 PMC11330628 source
Classified as probably not a substantial claim.
PremisecitationPU.1 function in maintaining HSC self-renewal capacity has been demonstrated.
“while its function in maintaining HSC self-renewal capacity has been further demonstrated 24.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Iwasaki H Somoza C Shigematsu H Duprez EA Iwasaki-Arai J Mizuno S Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation Blood 2005 106 1590 600 15914556 PMC1895212 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationUSP7 is linked to DNA repair and oncogenesis.
“linked to DNA repair 3 and oncogenesis 4”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [3] Pozhidaeva A Bezsonova I USP7: Structure, substrate specificity, and inhibition DNA Repair (Amst) 2019 76 30 9 30807924 PMC6481172 source
- cites [4] Al-Eidan A Wang Y Skipp P Ewing RM The USP7 protein interaction network and its roles in tumorigenesis Genes Dis 2022 9 41 50 35005106 PMC8720671 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPU.1 is a well-established master regulator of hematopoietic development, primarily governing myeloid differentiation.
“PU.1, a member of the ETS transcription factor family, is a well-established master regulator of hematopoietic development, primarily governing myeloid differentiation 23.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Le Coz C Nguyen DN Su C Nolan BE Albrecht AV Xhani S Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients J Exp Med 2021 218 e20201750 33951726 PMC8105723 source
The Introduction describes PU.1 as an important hematopoietic pioneer transcription factor and says its loss arrests both lymphoid and myeloid development. The Results section ‘PU.1 loss undermines B cell development’ also documents B-cell lineage arrest. These passages support a major role in hematopoietic development, but not the claim that PU.1 primarily governs myeloid differentiation. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPu.1 deficiency in HSCs impaired HSC self-renewal and long-term repopulation capacity, which could be rescued by PU.1 overexpression.
“Pu.1 deficiency in HSCs impaired HSC self-renewal and long-term repopulation capacity, which could be rescued by PU.1 overexpression 25.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [25] Staber PB Zhang P Ye M Welner RS Nombela-Arrieta C Bach C Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells Mol Cell 2013 49 934 46 23395001 PMC3644723 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral well-characterized USP7 substrates, including p53, PHF8, and PLK1, are known to be key regulators of cell cycle progression and cellular proliferation-processes fundamental to HSC maintenance.
“several well-characterized USP7 substrates, including p53 30, PHF8 31, and PLK1 32, are known to be key regulators of cell cycle progression and cellular proliferation—processes fundamental to HSC maintenance.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [30] Hu M Gu L Li M Jeffrey PD Gu W Shi Y Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway PLoS Biol 2006 4 e27 16402859 PMC1334386 source
- cites [31] Wang Q Ma S Song N Li X Liu L Yang S Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis J Clin Invest 2016 126 2205 20 27183383 PMC4887182 source
- cites [32] Peng Y Liu Y Gao Y Yuan B Qi X Fu Y USP7 is a novel Deubiquitinase sustaining PLK1 protein stability and regulating chromosome alignment in mitosis J Exp Clin Cancer Res 2019 38 468 31730000 PMC6858727 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIKZF1, EBF1, TCF3 and PAX5 are critical for B cell maturation and development.
“all of which are critical for B cell maturation and development, a process which is compromised in PB in Usp7-deleted mice.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [26] Yoshida T Georgopoulos K Ikaros fingers on lymphocyte differentiation Int J Hematol 2014 100 220 9 25085254 PMC4492456 source
The section “A new high-risk model of B-ALL supported by Ikaros mutations” (page unavailable) reports that Ikzf1 inactivation arrests B-cell differentiation at the large pre-B stage. “Priming lymphoid potential in multi-potent progenitors; the first task” also describes a role for E2A (TCF3) in lymphoid priming, but the retrieved passages do not establish the claim for EBF1 or PAX5. The statement about Usp7-deleted mice is not assessed as a finding attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [27] Boller S Ramamoorthy S Akbas D Nechanitzky R Burger L Murr R Pioneering Activity of the C-Terminal Domain of EBF1 Shapes the Chromatin Landscape for B Cell Programming Immunity 2016 44 527 41 26982363 source
- cites [28] Miyamoto S Urayama KY Arakawa Y Koh K Yuza Y Hasegawa D Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia Pediatr Hematol Oncol 2024 41 81 7 37129918 source
May combine two claims.
Findingown dataUSP7 directly binds and deubiquitinates PU.1, shielding it from proteasomal degradation.
“Mechanistically, USP7 directly binds and deubiquitinates the transcription factor PU.1, shielding it from proteasomal degradation.”
- Also stated in: § Introduction · boosted
“we demonstrated that USP7 binds, deubiquitinates and stabilizes PU.1”
Quote in the paperSubstantial claim- Rests on an assumption: PU.1 is a transcription factor essential for myeloid/lymphoid priming.
- Also stated in: § Introduction · boosted
May combine two claims.
Findingown dataUsp7-deficient HSCs display defective quiescence, reduced competitive repopulation capacity, and aberrant lineage differentiation.
“Usp7-deficient HSCs displayed defective quiescence, reduced competitive repopulation capacity, and aberrant lineage differentiation.”
Quote in the paperSubstantial claim- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
May combine two claims.
Findingown dataConditional Usp7 deletion in murine HSCs triggers rapid stem cell depletion, multilineage cytopenias, and systemic hematopoietic failure.
“Conditional Usp7 deletion in murine HSCs triggered rapid stem cell depletion, multilineage cytopenias, and systemic hematopoietic failure.”
- Also stated in: § Introduction · boosted
“we demonstrate that Usp7 depletion triggers HSC exhaustion, multilineage cytopenias, and hematopoietic collapse.”
Quote in the paperSubstantial claim- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
- Also stated in: § Introduction · boosted
May combine two claims.
FindingreasoningLoss of USP7 destabilizes PU.1, leading to suppressed expression of PU.1 target genes critical for HSC quiescence and lineage specification.
“Loss of USP7 destabilized PU.1, leading to suppressed expression of PU.1 target genes critical for HSC quiescence and lineage specification.”
Quote in the paperSubstantial claim- Rests on an assumption: PU.1 is a transcription factor essential for myeloid/lymphoid priming.
May combine two claims.
Findingown dataDonor contribution to PB lineages revealed a significant decrease in T cells and an almost complete loss of B cells and myeloid cells.
“Further analysis of donor contribution to PB lineages revealed a significant decrease in T cells and an almost complete loss of B cells and myeloid cells. (Fig. 4B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Usp7-/- HSCs, PU.1 target genes exhibited significant alterations, characterized by a marked downregulation of Myc and Gfi1, as well as a significant upregulation of Cdk1 and E2f1.
“but its target genes exhibited significant alterations, characterized by a marked downregulation of Myc and Gfi1, as well as a significant upregulation of Cdk1 and E2f1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUsp7 is relatively highly expressed at the single-cell level in mouse BM, with similar expression levels in individual LT-HSCs and early lineage-committed progenitor cells.
“Usp7 was relatively highly expressed at the single-cell level in mouse BM, with similar expression levels in individual LT-HSCs and early lineage-committed progenitor cells”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRed blood cell count, hemoglobin, and hematocrit remain unchanged in Usp7-/- mice.
“red blood cell count, hemoglobin, and hematocrit remain unchanged”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGST-USP7 but not GST alone pulled down Flag-PU.1, supporting a direct interaction of PU.1 with USP7 protein.
“an in vitro GST-pull down assay demonstrated that GST-USP7 but not GST alone, pulled down Flag-PU.1, supporting a direct interaction of PU.1 with USP7 protein.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPU.1 interacted with full-length USP7 and its MATH and UBL domains, but not with the catalytic domain; both the N-terminal MATH and C-terminal UBL domains are necessary for this interaction.
“PU.1 interacted with full-length USP7 and its MATH and UBL domains, but not with the catalytic domain, demonstrating that both the N-terminal MATH and C-terminal UBL domains are necessary for this interaction.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUsp7 is expressed across various tissues, organs, and hematopoietic cell subsets in mice, with relatively highest expression in BM and MEP cells.
“Usp7 was expressed across various tissues, organs, and hematopoietic cell subsets in mice, with relatively highest expression observed in the BM and megakaryocyte-erythroid progenitor (MEP) cells”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNeither the MATH- nor the UBL-deleted USP7 mutants could remove ubiquitin chains from PU.1, indicating that both domains are essential for this function.
“As shown in Fig. 6J, neither the MATH- nor the UBL-deleted USP7 mutants could remove ubiquitin chains from PU.1, indicating that both domains are essential for this function.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUsp7 mRNA is elevated in HSPCs and peaks specifically within the MEP subset in C57BL/6 mouse BM.
“expression was elevated in HSPCs and peaked specifically within the MEP subset”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataUSP7 is a critical regulator of HSC maintenance and hematopoietic homeostasis.
“Here, we define ubiquitin-specific protease 7 (USP7) as a critical regulator of HSC maintenance and hematopoietic homeostasis.”
- Also stated in: § Introduction · plain
“Here, we uncover USP7 as a guardian of HSC self-renewal.”
Quote in the paperSubstantial claim- Rests on an assumption: The contribution of deubiquitination to HSC self-renewal and lineage commitment remains unclear.
- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
- Rests on an assumption: HSC self-renewal and lineage commitment are tightly controlled by post-translational mechanisms.
- Also stated in: § Introduction · plain
May combine two claims.
Interpretationown dataUsp7 deficiency results in cytopenia and impairs HSC repopulation capacity and multi-lineage differentiation.
“Our findings reveal that Usp7 deficiency results in cytopenia and impairs HSC repopulation capacity and multi-lineage differentiation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe function of USP7 in hematopoiesis is lineage-specific and context dependent.
“the function of USP7 in hematopoiesis is lineage-specific and context dependent”
Quote in the paperSubstantial claim- Rests on an assumption: The role of USP7 in HSC maintenance remains unexplored.
May combine two claims.
Interpretationown dataUsp7 is essential for cell-autonomous HSC functionality and the consequences of Usp7 ablation on normal hematopoiesis become more pronounced under conditions of hematopoietic stress.
“These findings indicate that Usp7 is essential for cell-autonomous HSC functionality and the consequences of Usp7 ablation on normal hematopoiesis become more pronounced under conditions of hematopoietic stress.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPU.1 is a determinant factor for myeloid differentiation and plays a crucial regulatory role in hematopoietic development.
“PU.1 (also known as SPI1), which is a determinant factor for myeloid differentiation and plays a crucial regulatory role in hematopoietic development 17, 18”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17] Gangenahalli GU Gupta P Saluja D Verma YK Kishore V Chandra R Stem cell fate specification: role of master regulatory switch transcription factor PU.1 in differential hematopoiesis Stem Cells Dev 2005 14 140 52 15910240 source
- cites [18] Kastner P Chan S PU.1: a crucial and versatile player in hematopoiesis and leukemia Int J Biochem Cell Biol 2008 40 22 7 17374502 source
May combine two claims.
Interpretationown dataUsp7 deletion in HSCs reduces quiescence and promotes quiescent HSCs into cycling, increasing their propensity for division and proliferation.
“These results suggest that Usp7-/- HSCs exhibit reduced quiescence and an increased propensity for division and proliferation.”
- Also stated in: § Usp7 deficiency impairs HSCs pool and promotes quiescent HSCs into cycling · hedged
“Collectively, our data suggest that Usp7 deletion in HSCs promotes quiescent HSCs into cycling.”
Quote in the paperSubstantial claim- Also stated in: § Usp7 deficiency impairs HSCs pool and promotes quiescent HSCs into cycling · hedged
May combine two claims.
Study design and conductown dataUsp7 deletion in Mx1-Cre; Usp7fl/fl mice is highly efficient, with >80% mRNA reduction and drastic reduction in USP7 protein 2 weeks after final poly(I:C).
“A highly efficient deletion of Usp7 was achieved, as evidenced by genotyping, a dramatic reduction in mRNA expression (>80%) via qRT-PCR, and a corresponding drastic reduction in USP7 protein levels via western blotting 2 weeks following the final poly(I:C) injection”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataUSP7 stabilizes PU.1 via MATH/UBL domain-dependent deubiquitination, enabling PU.1 to enforce quiescence through transcriptional activation of Cdk1 and E2f1 and repression of cell cycle drivers like Myc and Gfi1.
“The finding that USP7 stabilizes PU.1 via MATH/UBL domain-dependent deubiquitination, enabling PU.1 to enforce quiescence through transcriptional activation of Cdk1 and E2f1 and repression of cell cycle drivers like Myc and Gfi1.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThis regulatory circuit explains the paradoxical hyperproliferation and functional decline of Usp7-/- HSCs, mirroring age-associated myeloid skewing linked to declining PU.1 levels.
“This regulatory circuit explains the paradoxical hyperproliferation and functional decline of Usp7-/- HSCs, mirroring age-associated myeloid skewing linked to declining PU.1 levels.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe requirement for USP7 is stage-specific, most pronounced in LT-HSCs, suggesting that these most primitive HSCs uniquely rely on USP7-mediated proteostasis to balance self-renewal and differentiation.
“Notably, the requirement for USP7 is stage-specific—which is most pronounced in LT-HSCs—suggesting that these most primitive HSCs uniquely rely on USP7-mediated proteostasis to balance self-renewal and differentiation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPU.1 is a critical USP7 target governing HSC self-renewal and differentiation, based on overlapping hematopoietic phenotypes between Usp7-/- and Pu.1-/- mouse models including loss of quiescence, myeloid-biased differentiation, and repopulation capacity failure.
“Our study identified PU.1 as a critical USP7 target governing HSC self-renewal and differentiation for the reason that we observed several overlapping hematopoietic phenotypes between Usp7-/- mouse models and reported Pu.1-/- mouse models, including loss of quiescence, myeloid-biased differentiation, and repopulation capacity failure.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The contribution of deubiquitination to HSC self-renewal and lineage commitment remains unclear.
“the contribution of deubiquitination to these processes remains unclear”
The paper relies on this without support.
The role of USP7 in HSC maintenance remains unexplored.
“However, its role in HSC maintenance—distinct from lineage-specific functions—remains unexplored.”
The paper relies on this without support.
PU.1 is a transcription factor essential for myeloid/lymphoid priming.
“PU.1, a transcription factor essential for myeloid/lymphoid priming”
The paper relies on this without support.
Post-translational mechanisms, particularly deubiquitination, remain poorly understood.
“post-translational mechanisms, particularly deubiquitination, remain poorly understood”
The paper relies on this without support.
HSC self-renewal and lineage commitment are tightly controlled by post-translational mechanisms.
“Hematopoietic stem cell (HSC) self-renewal and lineage commitment are tightly controlled by post-translational mechanisms”
The paper relies on this without support.
USP7's role in HSC self-renewal and hematopoiesis remains poorly understood.
“However, USP7's role in HSC self-renewal and hematopoiesis remains poorly understood.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
PU.1 regulation of four cell-cycle genes is reversed in the Discussion
MajorThe Results report that PU.1 protein decreases after Usp7 deletion while Myc and Gfi1 decrease and Cdk1 and E2f1 increase. The Discussion instead says PU.1 activates Cdk1 and E2f1 and represses Myc and Gfi1, the opposite direction implied by those results.
“enabling PU.1 to enforce quiescence through transcriptional activation of Cdk1 and E2f1 and repression of cell cycle drivers like Myc and Gfi1.”
“the protein abundance of PU.1 was substantially decreased in sorted Usp7-/- LK cells (Fig. 5G)”
CFU-M is identified as two different progenitor types
MinorThe Methods classify CFU-M among granulocyte-macrophage colonies, but the Results call CFU-M colonies megakaryocyte progenitors.
“particularly megakaryocyte progenitor cells (CFU-M colonies)”
“colony-forming units of granulocyte-macrophage lineages (CFU-GM, CFU-G, and CFU-M)”
Cites
p53 Regulates Hematopoietic Stem Cell Quiescence
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“This gap is striking, as USP7 substrates (e.g. p53 [8], PTEN [9]) regulate stem cell quiescence, which suggests broader roles in HSC integrity.”
Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.
Rosenbauer, F., Wagner, K., Kutok, J. L., Iwasaki, H., Le Beau, M. M., Okuno, Y., Akashi, K., Fiering, S., & Tenen, D. G. (2004) · Nature Genetics · doi:10.1038/ng1361 · Cited by 506 · cited 1× · see citing works
“In preleukemic states (e.g., MDS), where PU.1 downregulation permits clonal expansion [33-35], our discovery that USP7 is a critical stabilizer of PU.1 suggests that targeted activation of the USP7-PU.1 axis could represent a novel therapeutic strategy.”
Iwasaki, H., Somoza, C., Shigematsu, H., Duprez, E. A., Iwasaki-Arai, J., Mizuno, S.-I., Arinobu, Y., Geary, K., Zhang, P., Dayaram, T., et al. (2005) · Blood · doi:10.1182/blood-2005-03-0860 · Cited by 433 · cited 1× · see citing works
“Notably, hematopoietic-specific deletion of Pu.1 leads to the absolute loss of CMPs and CLPs, while its function in maintaining HSC self-renewal capacity has been further demonstrated [24].”
PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis
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“In preleukemic states (e.g., MDS), where PU.1 downregulation permits clonal expansion [33-35], our discovery that USP7 is a critical stabilizer of PU.1 suggests that targeted activation of the USP7-PU.1 axis could represent a novel therapeutic strategy.”
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“In addition, several well-characterized USP7 substrates, including p53 [30], PHF8 [31], and PLK1 [32], are known to be key regulators of cell cycle progression and cellular proliferation—processes fundamental to HSC maintenance.”
Haematopoietic stem cell self-renewal in vivo and ex vivo
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“Hematopoietic stem cells (HSCs) sustain lifelong blood production by balancing self-renewal with lineage commitment—a process whose dysregulation underlies bone marrow failure, leukemias, and myelodysplastic syndromes (MDS) [1, 2].”
Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.
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“In addition, several well-characterized USP7 substrates, including p53 [30], PHF8 [31], and PLK1 [32], are known to be key regulators of cell cycle progression and cellular proliferation—processes fundamental to HSC maintenance.”
Self-citationGöthert, J. R., Gustin, S. E., Hall, M. A., Green, A. R., Göttgens, B., Izon, D. J., & Begley, C. G. (2005) · Blood · doi:10.1182/blood-2004-08-3037 · Cited by 203 · cited 1× · see citing works
“Considering that the Mx1 promoter-driving Cre is expressed in both hematopoietic cells and stromal cells [11], we also crossed Usp7 fl/fl mice with a tamoxifen-induced HSPCs specific Scl-Cre strain [12] to get Scl-Cre; Usp7 fl/fl mice (Supplementary Fig.”
Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis
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“Hematopoietic stem cells (HSCs) sustain lifelong blood production by balancing self-renewal with lineage commitment—a process whose dysregulation underlies bone marrow failure, leukemias, and myelodysplastic syndromes (MDS) [1, 2].”
USP7: Structure, substrate specificity, and inhibition
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“1 deficiency in HSCs impaired HSC self-renewal and long-term repopulation capacity, which could be rescued by PU.1 overexpression [25].”
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“These include IKZF1 [26], EBF1 [27], TCF3 [28] and PAX5 [29], all of which are critical for B cell maturation and development, a process which is compromised in PB in Usp7 -deleted mice.”
USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin
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PU.1: A crucial and versatile player in hematopoiesis and leukemia
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“We noticed that PU.1 (also known as SPI1), which is a determinant factor for myeloid differentiation and plays a crucial regulatory role in hematopoietic development [17, 18], was consistently identified as one of the most abundant transcription factors regulated by USP7.”
PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
Chavez, J. S., Rabe, J. L., Loeffler, D., Higa, K. C., Hernandez, G., Mills, T. S., Ahmed, N., Gessner, R. L., Ke, Z., Idler, B. M., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201169 · Cited by 91 · cited 2× · see citing works
“Given that PU.1 is a critical determinant of HSC differentiation [19, 20] and considering the phenotypic parallels observed in both Pu.1 and Usp7 conditional knockout models (reduced quiescence and diminished repopulating capacity of HSCs), we examined whether PU.1 is regulated by USP7.”
Ikaros fingers on lymphocyte differentiation
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“These include IKZF1 [26], EBF1 [27], TCF3 [28] and PAX5 [29], all of which are critical for B cell maturation and development, a process which is compromised in PB in Usp7 -deleted mice.”
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“As a deubiquitinase, USP7 has been shown to be involved in regulating the stability and activity of various transcription factors [14-16].”
Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients
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“…results establish deubiquitination as a novel regulatory mechanism governing PU.1-dependent transcriptional programs in HSCs. PU.1, a member of the ETS transcription factor family, is a well-established master regulator of hematopoietic development, primarily governing myeloid differentiation [23].”
USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia
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“Co IP was conducted as described previously [6].”
InfluentialSelf-citationThe USP7 protein interaction network and its roles in tumorigenesis
Al-Eidan, A., Wang, Y., Skipp, P., & Ewing, R. M. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2020.10.004 · Cited by 57 · cited 1× · see citing works
“Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme (DUB) linked to DNA repair [3] and oncogenesis [4], stabilizes hematopoietic transcription factors like GATA1 [5], NOTCH1 [6], and IKZF1 [7], positioning it as a master regulator of differentiation.”
Self-citationPeng, Y., Liu, Y., Gao, Y., Yuan, B., Qi, X., Fu, Y., Zhu, Q., Cao, T., Zhang, S., Yin, L., et al. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1457-8 · Cited by 54 · cited 1× · see citing works
“In addition, several well-characterized USP7 substrates, including p53 [30], PHF8 [31], and PLK1 [32], are known to be key regulators of cell cycle progression and cellular proliferation—processes fundamental to HSC maintenance.”
Gangenahalli, G. U., Gupta, P., Saluja, D., Verma, Y. K., Kishore, V., Chandra, R., Sharma, R. K., & Ravindranath, T. (2005) · Stem Cells and Development · doi:10.1089/scd.2005.14.140 · Cited by 53 · cited 1× · see citing works
“We noticed that PU.1 (also known as SPI1), which is a determinant factor for myeloid differentiation and plays a crucial regulatory role in hematopoietic development [17, 18], was consistently identified as one of the most abundant transcription factors regulated by USP7.”
Li, C., Wu, B., Li, Y., Liu, Y., Wang, J., Xie, J., Xu, X., Tian, X., Ye, Z., Guan, J., et al. (2022) · Blood · doi:10.1182/blood.2022016112 · Cited by 39 · cited 1× · see citing works
“Western blotting analysis was performed as previously described [6, 10].”
Deubiquitylase USP7 regulates human terminal erythroid differentiation by stabilizing GATA1
Liang, L., Peng, Y., Zhang, J., Zhang, Y., Roy, M., Han, X., Xiao, X., Sun, S., Liu, H., Nie, L., et al. (2019) · Haematologica · doi:10.3324/haematol.2018.206227 · Cited by 37 · cited 2× · see citing works
“Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme (DUB) linked to DNA repair [3] and oncogenesis [4], stabilizes hematopoietic transcription factors like GATA1 [5], NOTCH1 [6], and IKZF1 [7], positioning it as a master regulator of differentiation.”
Self-citationSenescence is a Spi1-induced anti-proliferative mechanism in primary hematopoietic cells
Delestré, L., Cui, H., Esposito, M., Quiveron, C., Mylonas, E., Penard-Lacronique, V., Bischof, O., & Guillouf, C. (2017) · Haematologica · doi:10.3324/haematol.2016.157636 · Cited by 32 · cited 1× · see citing works
“Given that PU.1 is a critical determinant of HSC differentiation [19, 20] and considering the phenotypic parallels observed in both Pu.1 and Usp7 conditional knockout models (reduced quiescence and diminished repopulating capacity of HSCs), we examined whether PU.1 is regulated by USP7.”
PTEN in Regulating Hematopoiesis and Leukemogenesis
Wu, Y., Zhu, H., & Wu, H. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a036244 · Cited by 22 · cited 1× · see citing works
“This gap is striking, as USP7 substrates (e.g. p53 [8], PTEN [9]) regulate stem cell quiescence, which suggests broader roles in HSC integrity.”
Self-citationG2 arrest primes hematopoietic stem cells for megakaryopoiesis
Garyn, C. M., Bover, O., Murray, J. W., Ma, J., Salas-Briceno, K., Ross, S. R., & Snoeck, H.-W. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114388 · Cited by 14 · cited 1× · see citing works
“Recent studies have suggested that platelets can be produced directly from HSCs [13].”
Oxyberberine sensitizes liver cancer cells to sorafenib via inhibiting NOTCH1-USP7-c-Myc pathway
Sun, L., He, M., Li, F., Wu, D., Zheng, P., Zhang, C., Liu, Y., Liu, D., Shan, M., Yang, M., et al. (2024) · Hepatology Communications · doi:10.1097/hc9.0000000000000405 · Cited by 12 · see citing works
Deng, J., Liang, L., Yi, H. J., Su, T., Yang, Z. ‐., Nie, L., & Liu, J. (2020) · British Journal of Haematology · doi:10.1111/bjh.16549 · Cited by 11 · cited 1× · see citing works
“Previous studies have demonstrated its involvement in osteoblast/ adipocyte differentiation, terminal erythroid maturation, and megakaryocytic differentiation [5, 21, 22].”
“Hands-On” Regulation of B Cell Development by the Transcription Factor Pax5
Hagman, J. R., & Lukin, K. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.001 · Cited by 11 · cited 1× · see citing works
“These include IKZF1 [26], EBF1 [27], TCF3 [28] and PAX5 [29], all of which are critical for B cell maturation and development, a process which is compromised in PB in Usp7 -deleted mice.”
Stirewalt, D. L. (2004) · Nature Genetics · doi:10.1038/ng0604-550 · Cited by 10 · see citing works
Liu, M., Zhang, Y., Wu, Y., Jin, J., Cao, Y., Fang, Z., Geng, L., Yang, L., Yu, M., Bu, Z., et al. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.70960 · Cited by 10 · cited 1× · see citing works
“Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme (DUB) linked to DNA repair [3] and oncogenesis [4], stabilizes hematopoietic transcription factors like GATA1 [5], NOTCH1 [6], and IKZF1 [7], positioning it as a master regulator of differentiation.”
Self-citationUSP7 promotes IgA class switching through stabilizing RUNX3 for germline transcription activation
Zhao, B., Xia, Z., Yang, B., Guo, Y., Zhou, R., Gu, M., Liu, M., Li, Q., Bai, W., Huang, J., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114194 · Cited by 5 · see citing works
Self-citationUSP7 promotes IgA class switching through stabilizing RUNX3 for germline transcription activation.
Zhao, B., Xia, Z., Yang, B., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114315 · Cited by 4 · cited 1×
“As a deubiquitinase, USP7 has been shown to be involved in regulating the stability and activity of various transcription factors [14-16].”
Self-citationRare <i>TCF3</i> variants associated with pediatric B cell acute lymphoblastic leukemia
Miyamoto, S., Urayama, K. Y., Arakawa, Y., Koh, K., Yuza, Y., Hasegawa, D., Taneyama, Y., Noguchi, Y., Yanagimachi, M., Inukai, T., et al. (2024) · Pediatric Hematology and Oncology · doi:10.1080/08880018.2023.2201302 · Cited by 4 · cited 1× · see citing works
“These include IKZF1 [26], EBF1 [27], TCF3 [28] and PAX5 [29], all of which are critical for B cell maturation and development, a process which is compromised in PB in Usp7 -deleted mice.”
Gene Inactivation in Adult Long-Term Hematopoietic Stem Cells Using Inducible Mouse Models
Gudmundsson, K. O. (2021) · Methods in Molecular Biology · doi:10.1007/978-1-0716-1008-4_13 · cited 1×
“Considering that the Mx1 promoter-driving Cre is expressed in both hematopoietic cells and stromal cells [11], we also crossed Usp7 fl/fl mice with a tamoxifen-induced HSPCs specific Scl-Cre strain [12] to get Scl-Cre; Usp7 fl/fl mice (Supplementary Fig.”
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USP7 maintains hematopoietic stem cell dormancy and function by stabilizing HMGA2Preprint
Nouhaud, A., Anna, D., Bouttier, M., Rigaud, Q., Enfedaque, P., Somaï, H., Hébrard, S., Prade, N., Dufrechou, S., Musiani, D., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.03.731117
Ramani, M., Nguyen, N., Solis, J., Tenen, D. G., & Trinh, B. Q. (2026) · Biology · doi:10.3390/biology15181657
“USP7-mediated deubiquitination stabilizes PU.1 and sustains expression of target genes required for HSC quiescence, whereas loss of this stabilizing mechanism destabilizes PU.1, resulting in defective quiescence, impaired self-renewal, and multilineage hematopoietic failure [47].”
Influential
- Authors
- Shan, H., Zhang, Y., Xiao, X., Wu, W., Wang, Y., Zhu, C., Bai, W., Zhang, Z., Zhai, Y., Yang, L., Wu, Y., Lei, H., Xu, H., Luo, Y., Lu, L., & Wu, Y.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Guangzhou Women and Children Medical Center (CN)
- University of Cambridge (GB)
- Guangdong Academy of Medical Sciences (CN)
- Venue
- International Journal of Biological Sciences
- Publisher
- Ivyspring International Publisher
- Published
- 2026-01-01
- Volume
- 22
- Issue
- 2
- Pages
- 1036-1052
- ISSN
- 1449-2288 (ISSN-L)
- PMC
- PMC12781850
- OpenAlex
- W7118182537
- Cited by
- 2
- References
- 35
- Citations by year
- 2026: 2
- FWCI
- 9.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- International Journal of Biological Sciences (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- USP7, PU.1, hematopoietic stem cells, deubiquitination, protein stability, proteasomal degradation, stem cell quiescence, self-renewal
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Proto-Oncogene Protein Spi-1, Animals
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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