PELI2 regulates early B-cell progenitor differentiation and related leukemia via the IL-7R expression
Open accessAbstract
Little is known about the transition mechanisms that govern early lymphoid lineage progenitors from common lymphoid progenitors (CLP). Pellino2 (PELI2) is a newly discovered E3 ubiquitin ligase, which plays important roles in inflammation and the immune system. However, the physiological and molecular roles of PELI2 in the differentiation of immune cells are largely unknown. Here, by using a conditional knockout mouse model, we demonstrated that PELI2 is required for early B-cell development and stressed hematopoiesis. PELI2 interacted with and stabilized PU.1 via K63-polyubiquitination to regulate IL-7R expression. The defects of B-cell development induced by PELI2 deletion were restored by overexpression of PU.1. Similarly, PELI2 promoted TCF3 protein stability via K63-polyubiquitination to regulate IL-7R expression, which is required for the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. These results underscore the significance of PELI2 in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression, providing a potential therapeutic approach for BCP-ALL.
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TL;DR
PELI2 is required for early B-cell development and stressed hematopoiesis, where it stabilizes PU.1 via K63-linked polyubiquitination to maintain IL-7R expression. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), PELI2 instead stabilizes TCF3 to sustain IL-7R signaling and leukemia cell proliferation, and PELI2 inhibition reduces disease burden in xenografts.
Key findings
- Hematopoietic-specific PELI2 knockout mice showed leukopenia and reduced B cells (B220+) in blood, bone marrow, and spleen, with significantly reduced CLP and BLP populations and impaired pre-B colony formation. PELI2-deficient HSC showed defective self-renewal/reconstitution under stress, including an approximately 2.5-fold reduction in functional HSC by limiting-dilution assays and earlier bone marrow failure after 5-FU.
- Mechanistically, PELI2 interacted with PU.1 through its FHA domain and PU.1’s PEST domain, promoted K63-linked ubiquitination and PU.1 stability, and loss of PELI2 reduced PU.1, IL-7R expression, and IL-7R signaling (reduced phosphorylated Stat5 and AKT). IL-7R or PU.1 overexpression rescued B-cell differentiation and pre-B colony defects in PELI2 knockout cells/mice.
- In BCP-ALL, PELI2 and IL-7R were upregulated in patient samples (published RNA sequencing from 23 BCP-ALL patients and independent bone marrow mononuclear cells from 7 BCP-ALL patients). PELI2 knockdown reduced IL-7R expression, proliferation, and colony formation of BCP-ALL cells; TCF3 was required for IL-7R expression, and PELI2 stabilized TCF3 via K63-linked polyubiquitination.
- In Nalm-6 xenografts, all control Nalm-6-bearing mice died at around 26 days, whereas PELI2-silencing prolonged survival and reduced spleen size and leukemic infiltration; TCF3 or IL-7R overexpression reversed these suppression phenotypes. In primary human BCP-ALL xenografts, PELI2 knockdown prolonged survival and reduced human leukemic blasts in bone marrow and spleen.
Methods
- Conditional PELI2 knockout mice (PELI2fl/fl crossed with Vav-Cre) were used with bone marrow transplantation, competitive and limiting-dilution assays, 5-FU stress, and tamoxifen-inducible Ubc-cre-ERT2 chimeras. Analyses included flow cytometry, colony-forming assays, BrdU incorporation, qPCR, bulk RNA sequencing, immunoblotting, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays.
- Human BCP-ALL work used primary bone marrow mononuclear cells from 7 BCP-ALL patients, published RNA sequencing data from 23 BCP-ALL patients, Nalm-6 and 697 cell lines, and primary BCP-ALL CD34+ cells. Xenografts used irradiated NSG mice injected with 5×10^6 Nalm-6 cells or primary human BCP-ALL cells.
- Statistical analyses used unpaired two-tailed Student t tests unless otherwise indicated, with P<0.05 considered significant; survival curves used log-rank tests and some proliferation comparisons used two-way ANOVA.
Limitations
- The paper states that it cannot exclude the possibility that loss of PELI2 disrupts the transition from LMPP to CLP via PU.1, and that HSC defects in PELI2 knockout mice could be feedback cues from altered immunity/inflammation.
- Evident from the text: human primary BCP-ALL validation used a small sample (7 patients), and much of the mechanistic rescue and ubiquitination evidence is presented in Online Supplementary figures rather than fully in the main text.
- Evident from the text: the therapeutic implication of targeting PELI2 is supported by genetic knockdown/overexpression and xenograft models, not by a pharmacological PELI2 inhibitor.
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Claims the paper makes
13 of 17 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured
- Premisecitation
PU.1 plays a critical role in IL-7R expression specifically in B-cell lineages but not T-cell lineages.
“This is consistent with the critical role of PU.1 in IL-7R expression, which specifically occurred in B-cell lineages but not T-cell lineages.26,29”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [26] DeKoter RP Lee H-J Singh H. PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity. 2002; 16(2): 297- 309. 11869689 source
- cites [29] Anderson MK Hernandez-Hoyos G Diamond RA Rothenberg EV. Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. Development. 1999; 126(14): 3131- 3148. 10375504 source
The section on Ets factor expression during T-cell specification discusses PU.1 in B- and T-lineage development, but does not link it to IL-7R expression. A table in the section on lymphocyte-development landmarks mentions IL-7Rα mRNA in pre-NK cells, not PU.1-dependent regulation in B versus T cells. Searches for IL-7R and interleukin-7 receptor regulation found no passage addressing the attributed claim; page numbers were unavailable. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Premisecitation
IL-7R signaling mainly controls the proliferation and survival of early B-cell progenitor cells in normal B-cell development.
“IL-7R signaling mainly controls the proliferation and survival of early B-cell progenitor cells in normal B-cell development.28”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Miller JP Izon D DeMuth W Gerstein R Bhandoola A Allman D. The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. J Exp Med. 2002; 196(5): 705- 711. 12208884 PMC2193997 source
The Introduction says IL-7R engagement promotes proliferation and survival of B-lineage precursors. But the Discussion also identifies a critical role in early B-lineage differentiation and argues that IL-7 supplies more than survival signals, so the paper does not support describing proliferation and survival as its main functions. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
BCP-ALL is characterized by a block in lymphoid differentiation leading to accumulation of immature progenitor cells.
“BCP-ALL, which is characterized by a block in lymphoid differentiation leading to the accumulation of immature progenitor cells.37”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest. 2012; 122(10): 3407- 3415. 23023711 PMC3461902 source
- Findingown data
IL-7R overexpression significantly reverses the defect of B-cell differentiation in PELI2 CKO mice, indicated by increased B220+ cells and BLP in bone marrow and spleen and high lymphocyte levels in peripheral blood.
“As we expected, IL-7R overexpression significantly reversed the defect of B-cell differentiation in PELI2CKO mice, indicated by the increased number of B220+ cells and BLP in BM and spleen accompanied by the high levels of lymphocytes in PB (Figure 3H, I, Online Supplementary Figure S4E, F).”
Quote in the paperSubstantial claim - Findingown data
PU.1 target gene expression is transcriptionally repressed in PELI2 CKO mice.
“In line with this, PU.1 target gene expression was transcriptionally repressed in PELI2CKO mice (Online Supplementary Figure S5A).”
Quote in the paperSubstantial claim
- Findingown data
The numbers of SLAM-LSK (CD150+CD48-LSK) enriched HSC are significantly decreased in PELI2 CKO-BMT mice.
“Although the total LSK (Lin-Sca1+c-Kit+) cells were comparable (data not shown), the numbers of SLAM-LSK (CD150+CD48-LSK) indicating the enriched HSC were significantly decreased in CKO-BMT mice (Online Supplementary Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
CLP numbers are significantly reduced in PELI2 CKO bone marrow compared to WT mice.
“Although HSC (Lin-Sca1+c-Kit+) and HPC (Lin-Sca1-c-Kit+) were not apparently compromised in CKO mice (Online Supplementary Figure S1K), CLP in CKO BM were significantly reduced compared to that of WT mice (Figure 1E, F).”
Quote in the paperSubstantial claim - Findingown data
PELI2 CKO-BM reconstituted mice show reduced CLP compared to WT controls.
“Furthermore, CKO-BM reconstituted mice showed reduced CLP compared to WT controls (Figure 2D).”
Quote in the paperSubstantial claim - Findingown data
Co-immunoprecipitation assays demonstrate an interaction between PELI2 and PU.1.
“Co-immunoprecipitation (Co-IP) assays demonstrated an interaction between PELI2 and PU.1 (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Bulk RNA sequencing of B220+ bone marrow cells from PELI2 CKO and WT controls identified 537 differentially expressed genes (≥1.5-fold, P<0.05), including transcription factors related to early B-cell development such as EBF1, FOXO1, and PAX5.
“A total of 537 differentially expressed genes (DEG) were found (≥1.5-fold, P<0.05), including transcription factors related to early B-cell development such as EBF1, FOXO1, and PAX5 (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
The expression of ccnd3 is significantly reduced in PELI2 CKO CLP and B220+ bone marrow cells.
“In line with this, the expression of ccnd3, a proliferation-related gene, was significantly reduced in PELI2CKO CLP and B220+ BM cells (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
The frequency of B cells is significantly reduced in peripheral blood, bone marrow, and spleen of PELI2 CKO-BM reconstituted mice.
“The frequency of B cells was also significantly reduced in PB, BM and spleen of CKO-BM reconstituted mice (Figure 2C).”
Quote in the paperSubstantial claim - Findingown data
The frequency and numbers of B cells (B220+) in bone marrow are significantly decreased in PELI2 CKO mice compared to WT mice.
“The frequency and numbers of B cells (B220+) in BM was significantly decreased in CKO mice compared to that in WT mice (Figure 1C, D, Online Supplementary Figure S1E), while other lineage cells including T cells appeared normal in CKO mice (date not shown).”
Quote in the paperSubstantial claim - Findingown data
EBF1, FOXO1, and PAX5 are markedly down-regulated in CLP and B220+ bone marrow cells from PELI2 CKO mice.
“These genes were also confirmed to be markedly down-regulated in the CLP as well as B220+ BM cells from PELI2CKO mice (Figure 3D, Online Supplementary Figure S4C).”
Quote in the paperSubstantial claim - Findingown data
PELI2 overexpression protects PU.1 from time-dependent degradation upon cycloheximide treatment.
“In addition, PELI2 overexpression protected PU.1 from the time-dependent degradation upon cycloheximide (CHX) treatment (Online Supplementary Figure S5B).”
Quote in the paperSubstantial claim - Findingown data
PELI2 CKO mice succumb to bone marrow failure significantly earlier than WT littermates after 5-FU treatment.
“CKO mice exhibited a significant decrease in LSK expansion upon 5-FU administration (Figure 2E), and succumbed to BM failure significantly earlier than their WT littermates (Figure 2F).”
Quote in the paperSubstantial claim - Findingown data
PELI2 deficiency leads to increased quiescence in SLAM-LSK cells.
“Correspondingly, PELI2 deficiency led to the increased quiescence in SLAM-LSK (Online Supplementary Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
The leukopenia in PELI2 CKO mice is mainly caused by a reduction in B cells (B220+) in peripheral blood.
“In addition, the reduced numbers of lymphocytes accounted for the leukopenia phenotype in the CKO mice, which was mainly caused by the reduction in B cells (B220+) in the PB (Figure 1A, B, Online Supplementary Figure S1D).”
Quote in the paperSubstantial claim - Findingown data
PELI2 CKO HSC are efficiently engrafted in recipient bone marrow as WT controls, as indicated by homing assays.
“However, PELI2CKO HSC were efficiently engrafted in the recipient BM as the WT controls indicated by homing assays (Online Supplementary Figure S2D, E).”
Quote in the paperSubstantial claim - Findingown data
Loss of PELI2 leads to inhibition of IL-7R signaling, indicated by reduced phosphorylation of Stat5 and AKT.
“As expected, loss of PELI2 led to the inhibition of IL-7R signaling, as indicated by the reduced phosphorylation of Stat5 and AKT (Figure 3F, G).”
Quote in the paperSubstantial claim - Findingown data
B-cell proliferation in vivo is markedly restrained upon PELI2 deletion, as indicated by BrdU incorporation assays.
“Importantly, B-cell proliferation in vivo was markedly restrained upon the PELI2 deletion indicated by BrdU incorporation assays (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
Early T-cell development in the thymus is for the most part normal in PELI2 CKO mice.
“Although T cells were also reduced in CKO mice spleen, the early T-cell development in thymus was for the most part normal in CKO mice (Online Supplementary Figure S1H, I).”
Quote in the paperNot a substantial claim - Findingown data
All subpopulations of B cells are reduced in PELI2 CKO bone marrow compared to WT controls.
“Notably, all the subpopulations of B cells were reduced in PELI2CKO BM compared to WT controls (Online Supplementary Figure S1J).”
Quote in the paperSubstantial claim - Findingown data
PELI2 CKO mice exhibit a significant decrease in LSK expansion upon 5-FU administration.
“CKO mice exhibited a significant decrease in LSK expansion upon 5-FU administration (Figure 2E), and succumbed to BM failure significantly earlier than their WT littermates (Figure 2F).”
Quote in the paperSubstantial claim - Findingown data
Colony-forming assays with PELI2 CKO BM Lin- cells supplemented with IL-7 show significantly reduced colony number and size.
“This was further confirmed by the colony-forming assays with CKO BM Lin- cells supplemented with IL-7, which showed that the colony number and size were significantly reduced from CKO BM cells (Figure 1H).”
Quote in the paperSubstantial claim - Findingown data
PELI2 deletion has no effect on T-cell specific genes, including E2AE47, HES1, and NOTCH1.
“Although signals from IL-7R were shared in B/T cell-biased lymphoid progenitors from CLP, PELI2 deletion had no effect on the T-cell specific genes, including E2AE47, HES1, and NOTCH1 (Online Supplementary Figure S4D).”
Quote in the paperNot a substantial claim - Findingown data
TCF3 knockdown inhibits proliferation of Nalm-6 cells.
“TCF3 knockdown inhibited the proliferation of Nalm-6 cells”
Quote in the paperSubstantial claim - Findingown data
Replenishment of TCF3 reverses the suppression phenotypes of mice bearing PELI2-silencing Nalm-6, including shorter survival, enlarged spleen, and aggravated infiltrating Nalm-6 cells in spleen and BM.
“replenishment of TCF3 significantly reversed the suppression phenotypes of mice bearing PELI2-silencing Nalm-6, including the shorter survival (Figure 7B), enlarged spleen (Figure 7C, D), and aggravated infiltrating Nalm-6 cells in spleen and BM (Figure 7E).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
PELI2 overexpression promotes K63-linked ubiquitination of TCF3.
“Overexpression of PELI2 promoted K63-linked ubiquitination of TCF3 (Online Supplementary Figure S9F)”
Quote in the paperSubstantial claim - Findingown data
TCF3 binds the IL-7R promoter in Nalm-6 cells.
“The binding of TCF3 on the IL-7R promoter was further confirmed by ChIP analysis”
Quote in the paperSubstantial claim - Findingown data
The FHA domain of PELI2 is responsible for TCF3 binding.
“the FHA domain of PELI2 is responsible for the TCF3-binding (Online Supplementary Figure S9E)”
Quote in the paperNot a substantial claim - Findingown data
TCF3 overexpression induces an increase in IL-7R promoter-driven luciferase activity in HEK293T cells.
“Overexpression of TCF3 induced a marked increase in luciferase activity”
Quote in the paperSubstantial claim- Rests on an assumption: HEK293T cell-based luciferase reporter assays reflect regulation of the IL-7R promoter in BCP-ALL cells.
- Findingown data
PELI2 overexpression increases K63-linked ubiquitination of endogenous TCF3 in Nalm-6 cells.
“K63-ubiquitination of endogenous TCF3 was increased upon the overexpression of PELI2 in Nalm-6 cells.”
Quote in the paperSubstantial claim - Findingown data
PELI2 interacts with TCF3.
“Co-IP analysis demonstrated an interaction between PELI2 and TCF3 in HEK293T cells (Online Supplementary Figure S9D).”
- Also stated in: § PELI2 promoted TCF3 protein stability via K63-linked polyubiquitination in B-cell precursor acute lymphoblastic leukemia cells · boosted
“Their interaction was confirmed by endogenous coIP in Nalm-6 cells (Figure 6F).”
Quote in the paperSubstantial claim - Also stated in: § PELI2 promoted TCF3 protein stability via K63-linked polyubiquitination in B-cell precursor acute lymphoblastic leukemia cells · boosted
- Findingown data
Nalm-6 cell frequencies are lower in PELI2-silencing mice compared to controls.
“Nalm-6 cell frequencies were much lower in these mice compared to controls (Figure 7E).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
PELI2 overexpression enhances TCF3 protein stability in Nalm-6 cells.
“enhanced protein stability was observed in Nalm-6 cells with PELI2 overexpression (Online Supplementary Figure S9B)”
Quote in the paperSubstantial claim - Findingown data
TCF3 is positively correlated with PELI2 and IL-7R expression in BCP-ALL.
“TCF3 was positively correlated with the expression of PELI2 and IL-7R in BCP-ALL (Figure 6B, Online Supplementary Figure S8C, D)”
Quote in the paperSubstantial claim - Findingown data
PU.1 is relatively unaffected or undetectable in BCP-ALL.
“Given our finding that PU.1 is relatively unaffected or undetectable in BCP-ALL (Figure 5C, Online Supplementary Figure S7A)”
Quote in the paperSubstantial claim - Findingown data
PELI2 knockdown reduces K63-linked ubiquitination of TCF3 in Nalm-6 cells.
“PELI2 knockdown led to the reduced K63-ubiquitination but increased K48-ubiquitination of TCF3 in Nalm-6 cells (Figure 6H, Online Supplementary Figure S9H).”
Quote in the paperSubstantial claim - Findingnone given
The frequency of HSC in PELI2CKO mice BM is comparable to that of WT controls.
“Although the frequency of HSC in PELI2CKO mice BM is comparable to that of WT controls”
Quote in the paperSubstantial claim - Findingown data
MG132 pre-treatment abolishes the decrease in TCF3 protein induced by PELI2 knockdown.
“the decrease in TCF3 protein induced by PELI2 knockdown was clearly abolished by the pre-treatment of MG132 (Online Supplementary Figure S9C)”
Quote in the paperSubstantial claim - Findingown data
TCF3 knockdown significantly reduces IL-7R expression in Nalm-6 cells.
“TCF3 knockdown led to a significant reduction in IL-7R expression (Figure 6A, Online Supplementary Figure S8B)”
Quote in the paperSubstantial claim - Findingown data
TCF3 shows different expression from PU.1 during normal B-cell differentiation.
“TCF3 showed different expression with PU.1 during normal B-cell differentiation (Online Supplementary Figure S8H)”
Quote in the paperSubstantial claim - Findingown data
K48-linked ubiquitin approaches failed to detect any increase in ubiquitination of PU.1.
“Overexpression of PELI2 promoted K63-linked ubiquitination of PU.1 (Online Supplementary Figure S5C), whereas similar approaches using K48-linked ubiquitin failed to detect any increase in ubiquitination of PU.1 (Online Supplementary Figure S5D).”
Quote in the paperSubstantial claim - Findingown data
Binding of PU.1 to the IL-7R promoter is significantly reduced in B220+ bone marrow cells upon PELI2 deletion.
“We then analyzed chromatin occupancy of PU.1 on the IL-7R promotor region by ChIP, and found that the binding of PU.1 to the IL-7R promoter was significantly reduced in B220+ BM cells upon PELI2 deletion (Figure 4H).”
Quote in the paperSubstantial claim - Findingown data
PELI2 overexpression enhances TCF3-induced increase in IL-7R promoter luciferase activity.
“which was enhanced by PELI2 overexpression (Online Supplementary Figure S8 I)”
Quote in the paperSubstantial claim- Rests on an assumption: HEK293T cell-based luciferase reporter assays reflect regulation of the IL-7R promoter in BCP-ALL cells.
- Findingnone given
PELI2 is highly expressed in BCP-ALL.
“the high expression of PELI2 in BCP-ALL provides therapeutical benefit for targeting PELI2 in the treatment of BCP-ALL.”
Quote in the paperSubstantial claim - Findingown data
PELI2 ectopic expression increases TCF3 protein level.
“its ectopic expression resulted in an increase in TCF3 protein level”
Quote in the paperSubstantial claim - Findingown data
PELI2 knockdown reduces TCF3 protein stability in Nalm-6 cells.
“upon CHX treatment, TCF3 protein stability was reduced in Nalm-6 cells with PELI2 knockdown compared to control groups (Online Supplementary Figure S9A)”
Quote in the paperSubstantial claim - Findingown data
PELI2 knockdown reduces TCF3 binding to the IL-7R promoter in Nalm-6 cells.
“PELI2 knockdown greatly reduced their interaction in Nalm-6 cells (Figure 6E)”
Quote in the paperSubstantial claim - Findingown data
TCF3 overexpression aggravates the progression of Nalm-6-driven BCP-ALL in vivo.
“its overexpression aggravated the progression of Nalm-6-driven BCP-ALL in vivo (Figure 7B, Online Supplementary Figure S10A).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
IL-7R overexpression reverses PELI2 inhibition-induced suppression phenotypes in Nalm-6-driven BCP-ALL mice.
“A similar reversal of PELI2 inhibition-induced suppression phenotypes of Nalm-6-driven BCP-ALL was also observed in mice bearing PELI2-silencing Nalm-6 with IL-7R overexpression (Online Supplementary Figure S10B-F).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
PELI2-silencing Nalm-6-bearing mice exhibit significantly prolonged median survival compared to control Nalm-6-bearing mice.
“the mice bearing PELI2-silencing Nalm-6 exhibited significantly prolonged median survival (Figure 7B)”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
Ectopic expression of PELI2 attenuates the effect of vincristine chemotherapy on Nalm-6 cells.
“On the contrary, ectopic expression of PELI2 promoted the IL-7R signaling and proliferation of Nalm-6 cells (Online Supplementary Figure S7E, F), and even attenuated the effect of vincristine chemotherapy on Nalm-6 cells (Online Supplementary Figure S7G).”
Quote in the paperNot a substantial claim - Findingown data
The PELI2-binding domain in TCF3 maps to the interval between AD1 and AD2 domains.
“PELI2-binding domain in TCF3 was mapped to the interval between AD1 and AD2 domains (Figure 6G)”
Quote in the paperNot a substantial claim - Findingown data
PELI2 knockdown significantly reduces the colony formation ability of primary BCP-ALL CD34+ cells.
“Similarly, PELI2 knockdown also significantly reduced the colony formation ability of primary BCP-ALL CD34+ cells (Figure 5G).”
Quote in the paperSubstantial claim - Findingown data
Silencing of PELI2 dramatically inhibits the proliferation of Nalm-6 cells and 697 cells in BCP-ALL cells.
“Indeed, silencing of PELI2 dramatically inhibited the proliferation of Nalm-6 cells and 697 cells in BCP-ALL cells (Figure 5E, Online Supplementary Figure S7C).”
Quote in the paperSubstantial claim - Findingown data
PELI2 knockdown increases K48-linked ubiquitination of TCF3 in Nalm-6 cells.
“PELI2 knockdown led to the reduced K63-ubiquitination but increased K48-ubiquitination of TCF3 in Nalm-6 cells (Figure 6H, Online Supplementary Figure S9H).”
Quote in the paperSubstantial claim - Findingown data
PELI2 is highly expressed in parallel with IL-7R expression in peripheral blood samples from 23 BCP-ALL patients compared with normal individuals.
“We first analyzed the published RNA sequencing data from patients with BCP-ALL, and found that PELI2 is highly expressed in parallel with IL-7R expression in PB samples obtained from 23 BCP-ALL patients compared with the corresponding normal individuals (Online Supplementary Figure S7A).”
Quote in the paperSubstantial claim - Findingown data
PELI2 knockdown significantly prolongs survival of human BCP-ALL-bearing mice.
“PELI2-knockdown significantly prolonged the survival of BCP-ALL-bearing mice (Figure 7F).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
TCF3 overexpression restores IL-7R expression and Nalm-6 cell growth inhibited by PELI2 silencing.
“overexpression of TCF3 effectively restored the IL-7R expression and subsequent Nalm-6 cell growth inhibited by PELI2 silencing (Figure 6C, D)”
Quote in the paperSubstantial claim - Findingown data
PELI2-silencing reduces spleen size in Nalm-6-bearing mice compared to control.
“Compared with control Nalm-6-bearing mice, the spleen size of mice bearing PELI2-silencing Nalm-6 was significantly reduced (Figure 7C, D).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
Similar rescue for the defect of B-cell differentiation is observed in PELI2 CKO mice with PU.1 overexpression.
“Similar rescue for the defect of B-cell differentiation was also observed in CKO mice with PU.1 overexpression (Online Supplementary Figure S6).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of PELI2 promotes K63-linked ubiquitination of PU.1.
“Overexpression of PELI2 promoted K63-linked ubiquitination of PU.1 (Online Supplementary Figure S5C), whereas similar approaches using K48-linked ubiquitin failed to detect any increase in ubiquitination of PU.1 (Online Supplementary Figure S5D).”
Quote in the paperSubstantial claim - Findingown data
PELI2 overexpression does not increase K48-linked ubiquitination of TCF3.
“similar approaches using K48-linked ubiquitin failed to detect any increase in ubiquitination of TCF3 (Online Supplementary Figure S9G)”
Quote in the paperSubstantial claim - Findingown data
PELI2 silencing reduces TCF3 protein level.
“Silencing of PELI2 led to a dramatic reduction in TCF3”
Quote in the paperSubstantial claim - Findingown data
Overexpression of IL-7R effectively reverts the inhibitory proliferation of Nalm-6 cells induced by PELI2 knockdown in vitro.
“Notably, overexpression of IL-7R effectively reverted the inhibitory proliferation of Nalm-6 cells induced by PELI2 knockdown in vitro (Figure 5H).”
Quote in the paperSubstantial claim - Findingown data
PELI2CKO HSC exhibit notably impaired self-renewal and reconstitution upon challenge with 5-FU.
“PELI2CKO HSC exhibited notably impaired self-renewal and reconstitution upon the challenge of 5-FU.”
Quote in the paperSubstantial claim - Findingown data
The PELI2 FHA domain is responsible for the interaction with the PEST domain of PU.1.
“Co-IP assays with these truncations revealed that the PELI2 FHA domain was responsible for the interaction with the PEST domain of PU.1 (Figure 4D, F).”
Quote in the paperSubstantial claim - Findingown data
PELI2 silencing reduces the frequency of human leukemic blasts in the BM and spleen in recipient mice at two months post transplantation.
“PELI2 silencing led to a significant reduction in the frequency of human leukemic blasts in the BM and spleen in recipient mice at two months post transplantation (Figure 7G).”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Findingown data
T-lineage differentiation is unaffected by loss of PELI2.
“whereas T-lineage differentiation was unaffected.”
Quote in the paperSubstantial claim - Interpretationown data
PELI2 is required for the self-renewal of HSC in stressed hematopoiesis.
“These findings suggest that PELI2 is required for the self-renewal of HSC in stressed hematopoiesis.”
Quote in the paperSubstantial claim - Interpretationown data
The B-cell defect observed in PELI2 CKO mice is mainly due to the inhibition of early B-cell progenitor cell proliferation.
“These data indicated that the B-cell defect observed in PELI2CKO mice was mainly due to the inhibition of early B-cell progenitor cell proliferation.”
Quote in the paperSubstantial claim - Interpretationown data
TCF3 mediates the regulation of PELI2 on Nalm-6 cell proliferation via IL-7R expression.
“suggesting that TCF3 mediated the regulation of PELI2 on the Nalm-6 cell proliferation via IL-7R expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
Targeting PELI2 restricts B-cell precursor expansion via IL-7R inhibition.
“a proof of principle that targeting PELI2 restricts B-cell precursor expansion via IL-7R inhibition.”
Quote in the paperSubstantial claim- Rests on an assumption: Nalm-6 cells are a valid model of human B-cell precursor acute lymphoblastic leukemia.
- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Interpretationown data
TCF3 is required for IL-7R expression in Nalm-6 cells.
“indicating that TCF3 is required for IL-7R expression in Nalm-6 cells.”
Quote in the paperSubstantial claim - Premisecitation
An upstream regulatory element of PU.1 functions as a PU.1 enhancer in B cells but as a repressor in T-cell precursors.
“an upstream regulatory element of PU.1 functions as a PU.1 enhancer in B cells but as a repressor in T-cell precursors.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Rosenbauer F Owens BM Yu L. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nat Genet. 2006; 38(1): 27- 37. 16311598 source
- Interpretationown data
PELI2 inhibition reduces the human BCP-ALL burden in vivo.
“These results indicated that PELI2 inhibition reduced the human BCP-ALL burden in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Interpretationown data
PELI2 promotes PU.1 stability via ubiquitination to regulate IL-7R expression.
“Our study demonstrated that PELI2 promotes PU.1 stability via ubiquitination to regulate IL-7R expression.”
Quote in the paperSubstantial claim - Interpretationown data
PELI2 functions as a key mediator at the transition from the CLP to the earliest stage of B-cell specification via PU.1.
“Our data demonstrated that PELI2 functions as a key mediator at the transition from the CLP to the earliest stage of B-cell specification via PU.1”
Quote in the paperSubstantial claim - Interpretationown data
PELI2 regulates cell proliferation via IL-7R signaling in BCP-ALL cells.
“These findings suggested that PELI2 regulates cell proliferation via IL-7R signaling in BCP-ALL cells.”
Quote in the paperSubstantial claim - Interpretationown data
PELI2 regulates PU.1 protein stability via K63-linked ubiquitination.
“These data demonstrated that PELI2 regulates PU.1 protein stability via K63-linked ubiquitination.”
Quote in the paperSubstantial claim - Study design and conductown data
The deletion of PELI2 expression in the conditional knockout mice was confirmed by qPCR assays in bone marrow mononuclear cells.
“The deletion of PELI2 expression was confirmed by qPCR assays in the mononuclear cells from BM (Online Supplementary Figure S1B).”
Quote in the paperSubstantial claim - Interpretationown data
Inhibition of PELI2 suppresses the proliferation of BCP-ALL cells in vitro and in vivo.
“Inhibition of PELI2 suppressed the proliferation of BCP-ALL cells in vitro and in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: Nalm-6 cells are a valid model of human B-cell precursor acute lymphoblastic leukemia.
- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Interpretationown data
PELI2 is required for stressed hematopoiesis.
“indicating that PELI2 is required for stressed hematopoiesis.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 7
- May combine two claims. 31
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPU.1 is required for early lymphopoiesis, and its deficiency compromises differentiation of CLP into BLP.
“which is consistent with the role of PU.1 in early lymphopoiesis, the deficiency of which led to the compromised differentiation of CLP into BLP.31”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [31] Pang SHM de Graaf CA Hilton DJ. PU.1 is required for the developmental progression of multipotent progenitors to common lymphoid progenitors. Front Immunol. 2018; 9: 1264. 29942304 PMC6005176 source
The paper supports PU.1's role in early lymphopoiesis, but contradicts the claimed defect in CLP-to-BLP differentiation. In Results (“PU.1 Is Dispensable From the CLP Stage of Development”; page not provided), BLP frequency was equivalent with and without PU.1; the Discussion instead places PU.1's essential role before the CLP stage. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPU.1 is a master regulator in HSC cell fate decisions and homing through interaction with a variety of regulatory factors.
“PU.1 has also been identified as a master regulator in HSC cell fate decisions and homing through the interaction with a variety of regulatory factors.34,35”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [34] Etzrodt M Ahmed N Hoppe PS. Inflammatory signals directly instruct PU.1 in HSCs via TNF. Blood. 2019; 133(8): 816- 819. 30301719 source
The Introduction describes PU.1 as a central regulator of myeloid lineage decisions, and the Results and discussion link its regulation in HSCs to inflammatory signaling. The passages do not establish a role for PU.1 in HSC homing or show that it acts through interactions with a variety of regulatory factors. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [35] Chavez JS Rabe JL Loeffler D. PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress. J Exp Med. 2021; 218(6): e20201169. 33857288 PMC8056754 source
The Discussion describes PU.1 as a lineage-differentiation factor and reports its role in priming HSCs for myeloid differentiation. The Results discuss PU.1 binding to regulatory genes and note a previously reported complex with histone deacetylase proteins. Neither section establishes a role in HSC homing or shows that interactions with a variety of regulatory factors drive the claimed cell-fate and homing functions. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPU.1 is required for the developmental progression of CLP from LMPP, and its deficiency leads to reduced CLP and consequent B-cell development.
“PU.1 is also required for the developmental progression of CLP from LMPP, the deficiency of which leads to the reduced CLP and consequent B-cell development.31,32”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [31] Pang SHM de Graaf CA Hilton DJ. PU.1 is required for the developmental progression of multipotent progenitors to common lymphoid progenitors. Front Immunol. 2018; 9: 1264. 29942304 PMC6005176 source
- cites [32] Iwasaki H Somoza C Shigematsu H. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005; 106(5): 1590- 1600. 15914556 PMC1895212 source
The Discussion (page unavailable) reports a profound decrease in CLPs after PU.1 disruption and says this is compatible with impaired B-cell development. The Results (page unavailable) locate the developmental arrest at the transition from HSCs to CLPs, not specifically from LMPPs to CLPs. The paper also finds that PU.1 is not required for B-cell maturation once CLPs have formed. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationNalm-6-bearing mice exhibit rapid tumor burden and cell infiltration in spleen and BM.
“As previously reported,27 Nalm-6-bearing mice exhibited rapid tumor burden and cell infiltration in spleen and BM.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Tipanee J Samara-Kuko E Gevaert T Chuah MK VandenDriessche T. Universal allogeneic CAR T cells engineered with Sleeping Beauty transposons and CRISPR-CAS9 for cancer immunotherapy. Mol Ther. 2022; 30(10): 3155- 3175. 35711141 PMC9552804 source
- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
May combine two claims.
PremisecitationExcessive IL-7R signaling is oncogenic and responsible for resistance to conventional chemotherapy and targeted therapeutics.
“There is growing evidence indicating that excessive IL-7R signaling is oncogenic, being responsible for resistance to conventional chemotherapy and targeted therapeutics.38-40”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [38] Cramer SD Aplan PD Durum SK. Therapeutic targeting of IL-7Ralpha signaling pathways in ALL treatment. Blood. 2016; 128(4): 473- 478. 27268088 PMC4965903 source
The section on IL-7Rα pathway perturbations in T-ALL says increased IL-7R signaling may contribute to NOTCH1 oncogenicity. The PI3K/AKT/mTOR targeting section reports that pathway inhibition can modulate glucocorticoid resistance in T-ALL, but it does not establish that excessive IL-7R signaling is broadly responsible for resistance to conventional chemotherapy. The JAK/STAT targeting section discusses resistance to JAK inhibitors, but does not attribute that resistance generally to excessive IL-7R signaling. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [39] Cante-Barrett K Spijkers-Hagelstein JA Buijs-Gladdines JG. MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia. Leukemia. 2016; 30(9): 1832- 1843. 27174491 PMC5240021 source
The Introduction describes ectopic IL-7 expression as oncogenic, and the Discussion says IL7R mutations may promote leukemogenesis. The Results (Pharmacological inhibition of the IL7R pathway) report resistance of a mutant IL7Rα cell line to individual MEK, PI3K and AKT inhibitors. The paper does not establish that excessive IL-7R signaling causes resistance to conventional chemotherapy, or that it generally causes resistance to targeted therapies. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [40] Delgado-Martin C Meyer LK Huang BJ. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias. Leukemia. 2017; 31(12): 2568- 2576. 28484265 PMC5729333 source
The Results (‘The protective effect of IL7 is drug-specific’; page unavailable) show that IL7 protected T-ALL cells from dexamethasone and antagonized the HDAC inhibitor vorinostat. The same passage says IL7 did not protect against four other conventional chemotherapy drugs, so the claim overgeneralizes drug resistance. The paper discusses IL7 as a pro-survival factor and cites work on oncogenic IL7R mutations, but its reported results do not establish that excessive signaling is generally oncogenic. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTCF3 is genetically altered via translocations, deletions or mutations in BCP-ALL, leading to aberrant gene expression patterns in leukemic cells.
“TCF3, a defined transcription factor in normal B-cell differentiation, is genetically altered via translocations, deletions or mutations in BCP-ALL,5 leading to aberrant gene expression patterns in leukemic cells.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Somasundaram R Prasad MAJ Ungerbäck J Sigvardsson M. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia. Blood. 2015; 126(2): 144- 152. 25990863 PMC4505011 source
In “Disruption of transcription factor networks link development to disease” (indexed as Abstract; page unavailable), the paper describes TCF3 translocations that produce oncogenic fusion proteins. Table 1 (indexed as Abstract; page unavailable) also lists a TCF3 deletion in B-lineage ALL and a TCF3-PBX1 fusion in BCP-ALL. The paper does not specifically identify TCF3 mutations in BCP-ALL or establish that these alterations cause aberrant gene-expression patterns in leukemic cells. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataAlthough PU.1 mRNA level is unaltered, PU.1 protein level is clearly reduced in PELI2-deficient B220+ bone marrow cells.
“Although the mRNA level of PU.1 was unaltered, its protein level was clearly reduced in PELI2-deficient B220+ BM cells (Figure 4A, Online Supplementary Figure S5A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe absolute number of BLP cells is significantly reduced in PELI2 CKO mice, while ALP cell numbers are equal.
“Compared to the equal numbers of ALP cells, the absolute BLP cells that primarily act as early B-cell progenitors were significantly reduced in CKO mice (Figure 1G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHSC (Lin-Sca1+c-Kit+) and HPC (Lin-Sca1-c-Kit+) are not apparently compromised in PELI2 CKO mice.
“Although HSC (Lin-Sca1+c-Kit+) and HPC (Lin-Sca1-c-Kit+) were not apparently compromised in CKO mice (Online Supplementary Figure S1K), CLP in CKO BM were significantly reduced compared to that of WT mice (Figure 1E, F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 CKO bone marrow reconstituted mice exhibit persistently low lymphocyte counts but normal other blood cell values at four months post transplantation.
“CKO-BM reconstituted mice exhibited persistently low lymphocyte counts but other blood cell values were normal at four months post transplantation (Figure 2B, Online Supplementary Figure S2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 deficiency causes leukopenia in mice, with reduced white blood cells but unaffected red blood cells and platelets in peripheral blood.
“CKO mice clearly exhibited leukopenia, as demonstrated by the reduced white blood cells but unaffected red blood cells and platelets in the peripheral blood (PB) (Figure 1A, Online Supplementary Figure S1C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLoss of PELI2 leads to a slight increase in cell death in B220+ bone marrow cells, whereas PELI2 CKO CLP show comparable survival to WT.
“Loss of PELI2 led to a slight increase in cell death in B220+ BM cells, whereas PELI2CKO CLP showed comparable survival to WT (Online Supplementary Figure S4A, B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPELI2 CKO mice show reduced numbers of B cells in the spleen and a mild decrease in spleen weight.
“Similarly, CKO mice also showed reduced numbers of B cells in the spleen, as well as a mild decrease in spleen weight (Online Supplementary Figure S1F, G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 CKO HSC exhibit dramatically impaired proliferation but no relevant alteration in lineage commitments in recipient mice.
“Notably, PELI2CKO HSC exhibited dramatically impaired proliferation but no relevant alteration in the lineage commitments in the recipient mice (Figure 2J, Online Supplementary Figure S2G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 CKO-derived cells show a progressive decrease in peripheral blood in primary transplant recipients, with impaired reconstitution in bone marrow.
“PELI2CKO-derived cells showed a progressive decrease in PB in the primary transplant recipients, coinciding with a significantly impaired reconstitution in the BM (Figure 2H, I).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 deletion after tamoxifen injection impairs the reconstitution capacity of HSC and early B-cell development in adult mice.
“Similar to PELI2CKO mice, PELI2 deletion after injection of tamoxifen also impaired the reconstitution capacity of HSC and early B-cell development in adult mice (Online Supplementary Figure S3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 deficiency disrupts the sequential differentiation bias of B-cell progenitors, with slightly reduced pro-B and pre-B cells and a slight increase in mature B cells.
“The frequencies of pro-B cells and pre-B cells were slightly reduced in PELI2CKO BM while mature B cells showed a slight increase, indicating that PELI2 deficiency disrupted the sequential differentiation bias of B-cell progenitors (defined as B220+lgM-lgD-) (Online Supplementary Figure S1J).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPU.1 overexpression significantly restores reduced IL-7R expression, which successfully reverses the impaired pre-B CFU formation of bone marrow Lin- cells from PELI2 CKO mice.
“Importantly, PU.1 overexpression significantly restored the reduced IL-7R expression, which successfully reversed the impaired pre-B CFU formation of BM Lin- cells from PELI2CKO mice (Figure 4 I, Online Supplementary Figure S5F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEctopic expression of PELI2 promotes IL-7R signaling and proliferation of Nalm-6 cells.
“On the contrary, ectopic expression of PELI2 promoted the IL-7R signaling and proliferation of Nalm-6 cells (Online Supplementary Figure S7E, F), and even attenuated the effect of vincristine chemotherapy on Nalm-6 cells (Online Supplementary Figure S7G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 knockdown leads to a marked reduction in IL-7R expression, thereby inhibiting downstream signaling including phosphorylation of AKT and ERK, cMyc.
“PELI2 knockdown led to a marked reduction in IL-7R expression (Online Supplementary Figure S7B), thereby inhibiting its downstream signaling including the phosphorylation of AKT and ERK, cMyc (Figure 5D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA reduction in K63-linked ubiquitination but an increase in K48-linked ubiquitin of PU.1 is observed in B220+ bone marrow cells from PELI2 CKO mice.
“In line with this, a reduction in K63-linked ubiquitination but an increase in K48-linked ubiquitin of PU.1 were observed in B220+ BM cells from PELI2CKO mice (Figure 4G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPELI2 knockdown down-regulates Ki67 expression and represses DNA replication in Nalm-6 cells transduced with PELI2 shRNA.
“This was further confirmed by the down-regulated expression of Ki67 and repressed DNA replication in Nalm-6 cells transduced with PELI2 shRNA (Figure 5F, Online Supplementary Figure S7D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIndependent assays with bone marrow mononuclear cells from 7 BCP-ALL patients reveal significant upregulation of PELI2 expression and positive correlation with IL-7R.
“Consistent with this, our independent assays with BM mononuclear cells from 7 BCP-ALL patients also revealed a significant upregulation of PELI2 expression and positive correlation with IL-7R (Figure 5A, B), which was confirmed by the increase in both protein levels in the primary BCP-ALL cells (Figure 5C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPU.1 induces a marked increase in luciferase activity in HEK293T cells transduced with IL-7R promoter, which is further enhanced by PELI2 overexpression.
“PU.1 induced a marked increase in luciferase activity in HEK293T cells transduced with IL-7R promoter, which was further enhanced by PELI2 overexpression (Online Supplementary Figure S5E).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPELI2 is required for the commitment and proliferation of B-biased lymphoid progenitor cells from CLP.
“These findings suggested that PELI2 is required for the commitment and proliferation of B-biased lymphoid progenitor cells from CLP.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral transcription factors, including PU.1, RUNX1, and GA-binding protein transcription factor, control the expression of IL-7R.
“Several transcription factors have been seen to control the expression of IL-7R, including PU.1, RUNX1, and GA-binding protein transcription factor.26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] DeKoter RP Lee H-J Singh H. PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity. 2002; 16(2): 297- 309. 11869689 source
May combine two claims.
Interpretationown dataThe competitive disadvantage of PELI2 CKO HSC reconstitution is persistent in subsequent secondary recipients, indicating defective self-renewal of HSC in PELI2 CKO mice.
“The competitive disadvantage of PELI2CKO HSC reconstitution was persistent in subsequent secondary recipients (Online Supplementary Figure S2H, I), indicating the defective self-renewal of HSC in PELI2CKO mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPU.1 is expressed in HSC and exhibits a gradual decrease during subsequent differentiation into common lymphoid and myeloid progenitors.
“PU.1 is expressed in HSC and exhibits a gradual decrease during the subsequent differentiation into common lymphoid and myeloid progenitors.33”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Staber PB Zhang P Ye M. The Runx-PU.1 pathway preserves normal and AML/ETO9a leukemic stem cells. Blood. 2014; 124(15): 2391- 2399. 25185713 PMC4192750 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal studies were approved by the Institutional Animal Care and Use Committees at Shandong University.
“All animal studies were approved by the Institutional Animal Care and Use Committees at Shandong University.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataPELI2 promotes TCF3 protein stability via ubiquitination that is required for IL-7R expression in BCP-ALL cells.
“Our data demonstrated that PELI2 promotes TCF3 protein stability via ubiquitination that is required for the IL-7R expression in BCP-ALL cells (Figure 8).”
Quote in the paperSubstantial claim- Rests on an assumption: Nalm-6 cells are a valid model of human B-cell precursor acute lymphoblastic leukemia.
May combine two claims.
Interpretationown dataPELI2 is significant in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression.
“These results underscore the significance of PELI2 in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression, providing a potential therapeutic approach for BCP-ALL.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningThe differing commitment of CLP relies on the available transcription factors of IL-7R.
“it is reasonable to suppose that the differing commitment of CLP relies on the available transcription factors of IL-7R.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataPELI2 regulates early B-cell progenitor homeostasis and the progression of BCP-ALL by maintaining IL-7R expression via the ubiquitination of PU.1 and TCF3.
“In summary, we demonstrate that PELI2 regulated early B-cell progenitor homeostasis and the progression of BCPALL by maintaining IL-7R expression via the ubiquitination of PU.1 and TCF3, respectively (Figure 8).”
- Also stated in: § Discussion · plain
“PELI2 regulated early B-cell progenitor homeostasis and the progression of BCP-ALL by maintaining the IL-7R expression via the ubiquitination of PU.1 and TCF3, respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: Nalm-6 cells are a valid model of human B-cell precursor acute lymphoblastic leukemia.
- Rests on an assumption: NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
- Also stated in: § Discussion · plain
May combine two claims.
Interpretationown dataPELI2 promotes PU.1 stability via K63-linked ubiquitination to regulate IL-7R expression, which is required for early B-cell development.
“Collectively, these data demonstrated that PELI2 promotes PU.1 stability via K63-linked ubiquitination to regulate IL-7R expression, which is required for early B-cell development.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe PELI2-TCF3 axis regulates IL-7R expression, which is required for the proliferation of BCP-ALL cells.
“Collectively, these data demonstrated the PELI2-TCF3 axis regulates IL-7R expression, which is required for the proliferation of BCP-ALL cells.”
Quote in the paperSubstantial claim- Rests on an assumption: Nalm-6 cells are a valid model of human B-cell precursor acute lymphoblastic leukemia.
May combine two claims.
Interpretationown dataLoss of PELI2 impairs commitment and proliferation of early B-cell progenitors via PU.1 degradation and IL-7R downregulation.
“Loss of PELI2 leading to the degradation of PU.1, which in turn down-regulated the IL-7R expression, impaired the commitment and proliferation of early B-cell progenitors (Figure 8)”
Quote in the paperSubstantial claim
The paper relies on this without support.
PELI2's physiological and molecular roles in the development of immune cells are largely unknown.
“However, the physiological and molecular roles of PELI2 in the development of immune cells are largely unknown.”
The paper relies on this without support.
Nalm-6 cells are a valid model of human B-cell precursor acute lymphoblastic leukemia.
“To assess the effect of PELI2 repression on tumor progression of BCP-ALL, we established PELI2-silencing Nalm-6 cell lines using retroviral construct expressing shRNA targeting PELI2, and transplanted these cells into immunocompromised NOD scid gamma (NSG) mice (Figure 7A).”
The paper relies on this without support.
NSG mice transplanted with Nalm-6 or primary BCP-ALL cells recapitulate human BCP-ALL progression.
“Primary human BCP-ALL mononuclear cells were transduced with PELI2 shRNA and then transplanted into NSG mice.”
The paper relies on this without support.
HEK293T cell-based luciferase reporter assays reflect regulation of the IL-7R promoter in BCP-ALL cells.
“we performed the luciferase reporter assays in HEK293T cells driven by IL-7R promoter.”
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.
Figure 1G is cited for absolute BLP counts but reports percentages
MinorThe results cite Figure 1G as evidence that absolute BLP cell numbers were reduced, but the caption says Figure 1G quantifies percentages. The caption assigns cell numbers to Figure 1F.
“the absolute BLP cells that primarily act as early B-cell progenitors were significantly reduced in CKO mice (Figure 1G).”
“(G) Quantification of the percentage of BLP cells and ALP cells in the BM from indicated mice as in (E) (N=5).”
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DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3
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PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
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Flagged first, then by citations
Research works printed but not linked: 1
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Cited by
Sorted by citations
IL-7 in autoimmune diseases: mechanisms and therapeutic potential
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PELI2 inhibits colorectal cancer development through MAPK signaling pathway
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“Recent studies have also developed a conditional knockout model targeting PELI2, which provides a new tool for studying its role in lymphoid progenitor cell differentiation (Xu et al. 2024 ).”
Self-citation
- Authors
- Xu, Y., Zhou, Q., Wang, X., Zhang, A., Qi, W., Li, Y., Zheng, C., Guan, J., Sun, T., Li, J., Lu, C., Shen, Y., & Zhao, B.
- Affiliations
- Shandong University (CN)
- Qilu Hospital of Shandong University (CN)
- Heze Municipal Hospital (CN)
- Venue
- Haematologica
- Published
- 2023-12-07
- Volume
- 109
- Issue
- 6
- Pages
- 1800-1814
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC11141684
- OpenAlex
- W4389452182
- Cited by
- 3
- References
- 31
- Citations by year
- 2025: 3
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Haematologica (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- E3 ubiquitin ligase, B cell development, IL-7 receptor, PU.1, TCF3, K63-linked ubiquitination, protein stability, B-cell precursor acute lymphoblastic leukemia
- MeSH terms
- Animals, B-Lymphocytes, Cell Differentiation, Humans
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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