Type 1 interferon perturbates clonal competition by reshaping human blood development

IFNa did not alter CD90 expression after treatment in the HSPCs.

“Interestingly, while IFNa alters mouse HSC marker Sca-1 2 (rendering difficult the quantification of progenitor cell frequency changes by flow cytometric assessment in mice), IFNa did not alter CD90 expression after treatment in the HSPCs ( Fig. 2e, Supplementary Fig. 3c ).”

• cites [2] Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014). sourceCould not verify

  The Results section discusses blood-cell indexes and somatic mutations, not IFNα treatment or CD90 expression in HSPCs. Searches for the quoted claim and for IFNα, CD90, and Sca-1 found no passage in our copy that addresses the claim; the citing sentence instead points to its own figures. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

These findings contrasted with the more subtle transcriptional impact of CALR-mutations, since mutated and wildtype cells are co-mingled throughout differentiation.

“These findings contrasted with the more subtle transcriptional impact of CALR -mutations, since mutated and wildtype cells are co-mingled throughout differentiation 20,39 .”

• cites [20] Pourcelot, E. et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp. Hematol. 42, 360–368 (2014). sourceCould not verify

  The Discussion and “Impact of JAK2 status” sections address JAK2 V617F and cytokine profiles, not CALR mutations. Searches for CALR, transcriptional effects, and co-mingling of mutant and wild-type cells during differentiation found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [39] Van Egeren, D. et al. Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms. Cell Stem Cell 28, 514–523 (2021). sourceCould not verify

  The Results section (‘JAK2-Mutant HSPCs Exhibit Fate Bias’; page unavailable) reports similar expression profiles and intermixing for JAK2-V617F and wild-type cells, not CALR-mutant cells. Searches for CALR and calreticulin found no passage in our copy addressing CALR mutations’ transcriptional impact or their distribution through differentiation. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

The proportions of HSCs expressing G2/M/S-phase genes were enhanced upon IFNa treatment.

“Consistent with previous reports in mice 43 , the proportions of HSCs expressing G2/M/S-phase genes were enhanced upon IFNa treatment ( Fig. 2h,i) .”

• cites [43] Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016). sourceCould not verify

  The section on malignant-cell cell cycles (page unavailable) describes G1/S and G2/M signatures in melanoma cells, not HSCs. Searches for IFNa treatment, hematopoietic stem cells, and mouse HSC proliferation found no passage addressing the cited prior report. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

MYC targets were upregulated.

“Interestingly, MYC targets were also upregulated ( Fig. 2k, Supplementary Table 6 ), thus corroborating a previous report demonstrating that IFNa upregulates MYC protein, which was thus postulated to regulate the cell cycle entry of HSCs in mice 52 .”

• cites [52] Jakobsen, N. A. et al. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging. Cell Stem Cell 31, 1127–1144 (2024). sourceCould not verify

  The Results sections on TET2-mutant progenitors and inflammatory responses report changes in other gene signatures, but do not identify upregulated MYC targets. Searches for MYC and for IFN-α-induced MYC protein in mouse HSCs found no passage addressing either point. The cited paper therefore does not verify the MYC claim in our copy. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

MPN megakaryocytes exhibit higher expression of TGFB1.

“We and others have shown that MPN megakaryocytes indeed exhibit higher expression of TGFB1 20,50,51 , and thus downregulation of TGFB1 by IFNa may be a key mechanism of improvement in fibrosis frequently observed in patients treated with IFNa.”

• cites [20] Pourcelot, E. et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp. Hematol. 42, 360–368 (2014). sourceCould not verify

  The Methods section lists the 13 plasma cytokines measured, but TGFB1 is not among them. The Discussion links megakaryocytes to PDGF-BB synthesis, not to higher TGFB1 expression. Searches for TGFB1 and transforming growth factor beta found no passage addressing the attributed claim; page numbers were unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [50] Badalucco, S. et al. Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica 98, 514–517 (2013). sourcePartly supported

  Figure 2 and the results (p. 516) show that megakaryocytes from patients with primary myelofibrosis released more total and bioactive TGFβ1 than healthy controls. The paper does not establish higher TGFB1 gene expression or show that the finding extends to MPN megakaryocytes generally. The IFNa proposal follows the cited clause and is not treated as attributed to this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [51] Kaufmann, K. B. et al. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat. Immunol. 22, 723–734 (2021). sourceCould not verify

  The Extended Data Fig. 6 description (p. 5) mentions megakaryocytic cells only as an output of stem-cell differentiation assays; it does not address MPN megakaryocytes or TGFB1 expression. Searches for “MPN megakaryocytes TGFB1,” “transforming growth factor beta 1,” and “TGFB1” found no passage supporting the attributed comparison. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

TGFB1 was downregulated upon IFNa treatment.

“We also observed a downregulation of TGFB1 ( Supplementary Fig. 4b ), that encodes the pro-fibrotic cytokine TGFb established as one of the main inducers of myelofibrosis in patients with fibrotic-phase of MPN 50,51 .”

• cites [50] Badalucco, S. et al. Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica 98, 514–517 (2013). sourcePartly supported

  The citation is attached to the background claim about TGFβ and myelofibrosis, not to the citing authors’ observation of TGFB1 downregulation after IFNα treatment. The source describes TGFβ1 as having a crucial role in primary myelofibrosis pathogenesis, but its discussion of TGFβ1 promoting bone-marrow fibrosis is framed as a hypothesis, not an established finding that it is one of the main inducers. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [51] Kaufmann, K. B. et al. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat. Immunol. 22, 723–734 (2021). sourceCould not verify

  The cited paper’s PAK4-inhibition section (pp. 20–21) discusses hematopoietic stem-cell responses to a PAK4 inhibitor, not IFNα treatment. Searches for TGFB1 downregulation and IFNα treatment found no passage addressing the claim. In the citing sentence, references 50 and 51 appear attached to TGFβ’s role in myelofibrosis, while the downregulation is presented as the citing authors’ own observation. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

IFNa has been shown to induce HSC and progenitors into cell cycle entry.

“As IFNa has been shown to induce HSC and progenitors into cell cycle entry 43 , we posited that differential induction of progenitor subtypes into proliferation may underlie the shifts in differentiation.”

• cites [43] Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016). sourceCould not verify

  The section on cell-cycle heterogeneity describes cycling malignant melanoma cells, not hematopoietic stem cells or progenitors. Searches for IFN-alpha, HSCs, and hematopoietic progenitor cell-cycle entry found no passage in our copy addressing whether IFN-alpha induces those cells to enter the cell cycle; no page numbers were supplied. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Upregulation of CEBPB and CEBPD suggested a differentiation state into the granulocytic lineage.

“Upregulation of CEBPB and CEBPD ( Fig. 1e left, Supplementary Fig. 2d, Supplementary Table 3 ), implicated in emergency granulopoiesis 30 and granulopoiesis under cellular stress 31 respectively, suggested a differentiation state into the granulocytic lineage.”

• cites [30] Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865–868 (2017). sourceCould not verify

  The passages on immune-cell characterization discuss CITE-seq markers and NK-cell subsets, not CEBPB or CEBPD. Searches for those genes, emergency granulopoiesis, and granulocytic-lineage differentiation found no passage in our copy addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [31] Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018). sourceCould not verify

  The Results section discusses hematopoietic progenitor lineages, but does not link CEBPB or CEBPD upregulation to granulocytic differentiation. Searches for those genes, emergency granulopoiesis, and granulopoiesis under cellular stress found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

CD9 and VWF are closely associated with MkP differentiation.

“In the MkPs, we identified a downregulation of CD9 and VWF , closely associated with MkP differentiation 46-49 , upon IFNa treatment ( Supplementary Fig. 4b ) which is consistent with the decrease in the proportion of MkP observed after IFNa treatment.”

• cites [46] Nam, A. S. et al. Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation. Nat. Genet. 54, 1514–1526 (2022). sourcePartly supported

  The Results section on the DNMT3A-mutated bone marrow sample says CD9 expression has been linked with megakaryocytic differentiation priming and examines it along that differentiation trajectory. The passages found do not establish the same association for VWF; they also do not address IFNa treatment, which the citing sentence presents as its own finding. No page number was provided for these passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [47] Nie, Y., Han, Y. C. & Zou, Y. R. CXCR4 is required for the quiescence of primitive hematopoietic cells. J. Exp. Med. 205, 777–783 (2008). sourceCould not verify

  The Results and Discussion passages address CXCR4-dependent hematopoietic stem-cell quiescence and differentiation, not MkP differentiation. Searches for CD9, VWF, megakaryocyte progenitors, and related terms found no passage connecting either marker to MkP differentiation. Page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [48] Ciurea, S. O. et al. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110, 986–993 (2007). sourceNot checked — no full text of the source
• cites [49] Chagraoui, H. et al. Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood 100, 3495–3503 (2002). sourceCould not verify

  The Marrow cell preparation and infection section describes progenitor-cell enrichment, and the Pathological changes in tissues section describes megakaryocyte proliferation, but neither links CD9 or VWF to MkP differentiation. Searches for CD9, VWF, and megakaryocytic differentiation found no passage addressing that link; page numbers were unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Downregulation of TGFB1 by IFNa may be a key mechanism of improvement in fibrosis frequently observed in patients treated with IFNa.

“We and others have shown that MPN megakaryocytes indeed exhibit higher expression of TGFB1 20,50,51 , and thus downregulation of TGFB1 by IFNa may be a key mechanism of improvement in fibrosis frequently observed in patients treated with IFNa.”

• cites [20] Pourcelot, E. et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp. Hematol. 42, 360–368 (2014). sourceCould not verify

  The citation is attached to the statement that MPN megakaryocytes have higher TGFB1 expression, but the indexed paper does not address TGFB1 expression. Its cytokine-assay methods list IFN-gamma, not IFN-alpha or TGFB1; the treatment discussion concerns JAK inhibitors, not IFN-alpha or fibrosis improvement. Searches for TGFB1 in megakaryocytes and for IFN-alpha–related fibrosis found no supporting passage. The proposed mechanism after the citation is the citing authors’ inference. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [50] Badalucco, S. et al. Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica 98, 514–517 (2013). sourceSupported
• cites [51] Kaufmann, K. B. et al. A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness. Nat. Immunol. 22, 723–734 (2021). sourceCould not verify

  The citation in the printed sentence follows the claim that MPN megakaryocytes have higher TGFB1 expression; the IFNa–fibrosis mechanism is the citing authors’ subsequent inference. Our copy’s PAK4-inhibition section (pp. 20–21) discusses hematopoietic stem-cell cycling, not either TGFB1 expression in MPN megakaryocytes or IFNa-associated fibrosis improvement. Searches for TGFB1, MPN megakaryocytes, and IFNa found no passage addressing those points. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

In HSCs, CXCR4 gene expression was downregulated upon IFNa treatment.

“In HSCs, we identified a downregulation of CXCR4 gene expression ( Fig. 2j, Supplementary Table 5) , a key regulator of HSC quiescence 45 , which may thus be involved in cell cycle entry of HSCs.”

• cites [45] García-García, I. et al. Pharmacokinetic and pharmacodynamic comparison of two ‘pegylated’ interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study. BMC Pharmacol. 10, 15 (2010). sourceCould not verify

  Citation 45 is attached to the description of CXCR4 as a key regulator of HSC quiescence; the downregulation is presented as the citing authors’ own finding. The cited paper’s Methods and Discussion describe interferon-response measurements in healthy volunteers, but passages retrieved for CXCR4, HSCs, and quiescence do not address that regulatory role. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

In MkPs, CD9 and VWF were downregulated upon IFNa treatment.

“In the MkPs, we identified a downregulation of CD9 and VWF , closely associated with MkP differentiation 46-49 , upon IFNa treatment ( Supplementary Fig. 4b ) which is consistent with the decrease in the proportion of MkP observed after IFNa treatment.”

• cites [46] Nam, A. S. et al. Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation. Nat. Genet. 54, 1514–1526 (2022). sourcePartly supported

  The Results section (page unavailable) links CD9 expression to megakaryocytic priming, supporting the differentiation-related point to which the citation is attached. It does not establish the same link for VWF. The IFNa-associated downregulation is presented as the citing authors’ own finding, not as a result attributed to this source. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [47] Nie, Y., Han, Y. C. & Zou, Y. R. CXCR4 is required for the quiescence of primitive hematopoietic cells. J. Exp. Med. 205, 777–783 (2008). sourceCould not verify

  The citation is attached to the statement that CD9 and VWF are associated with MkP differentiation; the IFNa-treatment result is presented as the citing authors’ own finding. The cited paper’s Results and Discussion passage on cell-cycle regulation concerns CXCR4, CXCL12, and p57kip2 in primitive hematopoietic cells. Searches for CD9, VWF, MkPs, and IFNa found no passage addressing the cited association or the treatment result. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [48] Ciurea, S. O. et al. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110, 986–993 (2007). sourceNot checked — no full text of the source
• cites [49] Chagraoui, H. et al. Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood 100, 3495–3503 (2002). sourceCould not verify

  The cited paper’s Marrow cell preparation and infection and Discussion passages concern thrombopoietin-transduced mouse cells and TGF-β1, not IFNa treatment of MkPs. Searches for CD9, VWF, and interferon-alpha found no passage addressing their downregulation. The citing sentence points to its own Supplementary Fig. 4b for that observation. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Mutated and wildtype HSPCs were co-mingled throughout differentiation both at baseline and upon IFNa therapy.

“Consistent with our previous results 20 , the mutated and wildtype HSPCs were co-mingled throughout differentiation both at baseline and upon IFNa therapy ( Fig. 3a, Supplementary Fig. 5a) .”

• cites [20] Pourcelot, E. et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp. Hematol. 42, 360–368 (2014). sourceCould not verify

  The Impact of JAK2 status section compares plasma cytokine concentrations in JAK2 V617F-positive and -negative patients, not the positions of mutated and wildtype HSPCs during differentiation. Searches for co-mingling, HSPC differentiation, and IFNα therapy found no passage addressing the claim; the paper’s interferon measurement concerns IFN-γ. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

CALR mutations enhance the unfolded protein response, specifically the pro-survival IRE1-XBP1 axis.

“CALR mutations enhance the unfolded protein response (UPR), specifically the pro-survival IRE1-XBP1 axis 20”

• cites [20] Pourcelot, E. et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp. Hematol. 42, 360–368 (2014). sourceCould not verify

  The Discussion (page unavailable) describes cytokine profiling in polycythemia vera and essential thrombocythemia, including responses associated with JAK2 V617F. Searches for CALR mutations, the unfolded protein response, and IRE1-XBP1 found no passage in our copy addressing the claimed mechanism. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

The rate of cell cycle entry of the mutated cells was already near or at the point of saturation due to the CALR mutation.

“However, in contrast to the other myeloid progenitors, within the MkPs (wherein the CALR mutation exerts the greatest phenotypic effects due to the activation of the thrombopoietin receptor 21,54-57 ), the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline ( Fig. 3e ), suggesting that the rate of cell cycle entry of the mutated cells was already near or at”

• cites [21] Fisher, D. A. C., Fowles, J. S., Zhou, A. & Oh, S. T. Inflammatory pathophysiology as a contributor to myeloproliferative neoplasms. Front. Immunol. 12, 683401 (2021). sourceCould not verify

  The section “Hyperactivation of JAK2 or MPL Causes Myeloproliferation, Cytokine Production, and Myelofibrosis” explains that mutant CALR activates the thrombopoietin receptor MPL, but does not address whether cell-cycle entry is near saturation. Searches for CALR-mutant progenitor cell-cycle entry and IFNα response found no passage supporting that inference. In the citing sentence, the saturation statement appears to be the citing authors’ interpretation, not the point attached to the citation. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [54] Sirenko, M. et al. Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia. Cell Stem Cell 32, 1102–1121 (2025). sourceCould not verify

  The Results section on intratumoral transcriptional heterogeneity discusses cell-cycle activity in NRAS-mutant AML clones, not CALR-mutant megakaryocyte progenitors. Searches for CALR, IFNa, and saturation of cell-cycle entry found no passage in our copy addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [55] Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020). sourceCould not verify

  The passages on cycling endocrine progenitors (pp. 7–8) concern scVelo’s identification of cell-cycle states, not CALR-mutated megakaryocyte progenitors. Searches for CALR, IFNa, and saturation of cell-cycle entry found no passage addressing the claim in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [56] La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018). sourceCould not verify

  The Abstract discusses RNA velocity and cell-cycle dynamics during chromaffin differentiation, and the Extended Data discusses cell-cycle effects in intestinal cells. Neither addresses CALR-mutated megakaryocyte progenitors or saturation of cell-cycle entry; searches for CALR mutation, saturation, and IFNa-related proliferation found no relevant passage in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [57] Wolf, F. A. et al. PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells. Genome Biol. 20, 59 (2019). sourceCould not verify

  The Results section discusses PAGA analyses of hematopoietic differentiation and megakaryocyte progenitors, but not CALR-mutated cells or their proliferation. Searches for CALR, IFNa, and saturation of cell-cycle entry found no passage addressing the claim; the copy is not truncated. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Within the MkPs, the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline.

“However, in contrast to the other myeloid progenitors, within the MkPs (wherein the CALR mutation exerts the greatest phenotypic effects due to the activation of the thrombopoietin receptor 21,54-57 ), the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline ( Fig. 3e ), suggesting that the rate of cell cycle entry of the mutated cells was already near or at”

• cites [21] Fisher, D. A. C., Fowles, J. S., Zhou, A. & Oh, S. T. Inflammatory pathophysiology as a contributor to myeloproliferative neoplasms. Front. Immunol. 12, 683401 (2021). sourcePartly supported

  The citation is attached to the parenthetical explanation about CALR, not to the IFNα proliferation result, which the citing sentence attributes to its own Fig. 3e. In “Hyperactivation of JAK2 or MPL Causes Myeloproliferation, Cytokine Production, and Myelofibrosis” (page unavailable), the source says mutant CALR activates the thrombopoietin receptor MPL and that MPL is expressed in the megakaryocytic lineage. It does not establish that CALR has its greatest phenotypic effects specifically in MkPs. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [54] Sirenko, M. et al. Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia. Cell Stem Cell 32, 1102–1121 (2025). sourceCould not verify

  The Results sections on IDH-mutant AML discuss interferon-related gene expression at relapse and proliferation-associated pathways in particular clones, but not IFNα treatment of CALR-mutant MkPs. Searches for CALR, thrombopoietin-receptor activation, and modest proliferation relative to baseline found no passage addressing the claim. Page numbers were not supplied in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [55] Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020). sourceCould not verify

  The cited paper’s ‘Identifying reaction rates in transient cell populations’ section (p. 4) concerns simulated RNA-splicing kinetics, not IFNa-treated MkPs. Searches for MkPs, CALR mutation, IFNa, and the thrombopoietin receptor found no passage in our copy addressing the claimed proliferation comparison. In the citing sentence, the numbered citations attach to the parenthetical about CALR, while the proliferation comparison points to the citing paper’s Fig. 3e. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [56] La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018). sourceCould not verify

  The cited paper’s Extended Data discusses RNA velocity in mouse bone marrow cells, but it does not address IFNa treatment or proliferation of CALR-mutated MkPs. Searches for CALR, the thrombopoietin receptor, IFNa, and the claimed baseline comparison found no supporting passage. In the citing sentence, the numbered citations attach to the parenthetical about CALR, while Fig. 3e is given for the proliferation result. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [57] Wolf, F. A. et al. PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells. Genome Biol. 20, 59 (2019). sourceCould not verify

  The Results section on hematopoiesis discusses progenitor-cell trajectories and gene-expression changes, not IFNa treatment or proliferation in CALR-mutated MkPs. Searches for IFNa, CALR, and thrombopoietin-receptor effects found no passage addressing the claimed baseline comparison. In the quoted sentence, the numbered citations appear beside the separate CALR-receptor explanation; the IFNa comparison points to Fig. 3e. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

There is a potential causal link between UPR and IFN activation.

“supporting a potential causal link between UPR and IFN activation 62”

• cites [62] Zeng, A. G. X. et al. Human haematopoietic stem cells remember inflammatory stress. Nature 655, 458–467 (2026). sourceCould not verify

  The sections on inflammatory response priming and HSC-II memory describe inflammatory signalling in haematopoietic stem cells, but do not connect it to a UPR. Searches for “UPR,” “unfolded protein response,” and interferon activation with endoplasmic-reticulum stress found no passage addressing the proposed causal link. The available copy therefore does not verify the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

At baseline, the CALR-mutation induced proliferation in the HSCs and the myeloid cell lineages (i.e. the granulo-monocytic and megakaryocytic-erythroid lineages) but not in the lymphoid progenitors.

“At baseline, the CALR -mutation induced proliferation in the HSCs and the myeloid cell lineages (i.e. the granulo-monocytic and megakaryocytic-erythroid lineages) but not in the lymphoid progenitors ( Fig. 3e ), consistent with our previous reporting 20 .”

• cites [20] Pourcelot, E. et al. Cytokine profiles in polycythemia vera and essential thrombocythemia patients: clinical implications. Exp. Hematol. 42, 360–368 (2014). sourceCould not verify

  The paper’s discussion addresses cytokine profiles and JAK2 V617F in polycythemia vera and essential thrombocythemia, not CALR-driven proliferation. Searches for CALR, hematopoietic stem cells, myeloid lineages, and lymphoid progenitors found no passage addressing the claimed lineage-specific effect; page numbers were unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

The distributions of these differentially upregulated TFs were highly enriched in the most quiescent HSCs with the highest overall expression of AVP and CD90 (HSC1).

“Strikingly, the distributions of these differentially upregulated TFs were highly enriched in the most quiescent HSCs with the highest overall expression of AVP and CD90 (HSC1, Fig. 1f,g, Supplementary Fig. 2c ), driving the transcriptional similarities of the IGPs and HSC1 as revealed by their proximity on the UMAP space.”

Downregulated genes in the TNFa pathway included NFKB1, VEGFA, MAP3K8, as well as IL1B.

“Downregulated genes in the TNFa pathway included NFKB1 , VEGFA , MAP3K8, as well as IL1B , that encodes the pro-inflammatory cytokine IL-1b ( Fig. 2l, Supplementary Table 6) .”

An unknown cluster (Cluster X), adjacent to the HSCs in the UMAP space, resembled the IMPs immunophenotypically based on CD38 mid, CD90 lo, and CD45RA mid expression.

“We also identified an unknown cluster (Cluster X), adjacent to the HSCs in the UMAP space ( Fig. 1c ), that resembled the IMPs immunophenotypically based on CD38 mid , CD90 lo , and CD45RA mid expression ( Fig. 1d ).”

Gene set enrichment analysis between baseline and IFNa-treated cells revealed a global decrease in TGFb signaling pathway across multiple HSPC subsets, including downregulation of THBS1 and SERPINE1.

“Consistent with downregulation of TGFB1 gene itself, gene set enrichment analysis between baseline and IFNa-treated cells revealed a global decrease in TGFb signaling pathway across multiple HSPC subsets, including downregulation of THBS1 and SERPINE1 ( Fig. 2k, Supplementary Table 6) .”

The proportion of TdT+, CD19+ cells within CD34+ cells increased in IFNa-treated bone marrow compared to non-IFNa exposed samples.

“Indeed, we identified that the proportion of TdT + , CD19 + cells within CD34 + cells increased in IFNa-treated bone marrow compared to non-IFNa exposed samples ( Fig. 2f) .”

The proportions of MEPs and MkPs in CD34+ cells could model the patient's platelet counts (P = 0.0071, F-test).

“Consistent with this hypothesis, the proportions of MEPs and MkPs in CD34 + cells could model the patient's platelet counts (P = 0.0071, F-test, Fig. 2g ), thus supporting a novel model of re-balancing the differentiation landscape as a mode of therapeutic efficacy of IFNa.”

There was a global increase in proliferation across the progenitor lineages, including granulo-monocytic, erythroid, and lymphoid subsets, upon IFNa treatment.

“Surprisingly, we identified a global increase in proliferation across the progenitor lineages, including granulo-monocytic, erythroid, and lymphoid subsets ( Fig. 2h,i) .”

Genes commonly regulated across multiple progenitor subsets upon IFNa administration include the canonical IFNa genes ISG15, IFITM3, IFI6 and EPSTI1.

“We identified genes commonly regulated across multiple progenitor subsets upon IFNa administration, including the canonical IFNa genes, such as ISG15, IFITM3, IFI6 and EPSTI1 ( Fig. 2j, Supplementary Table 5) .”

There was a significant overlap between the IFNa-downregulated genes in the TNFa signaling and the genes that are upregulated in the IGPs (P = 1.6 x 10^-5, hypergeometric test).

“In fact, we observed a significant overlap between the IFNa-downregulated genes in the TNFa signaling and the genes that are upregulated in the IGPs ( Fig. 2l , Supplementary Table 6, P = 1.6 x 10 -5 , hypergeometric test).”

HSCs exhibited an increased protein expression of CD38 and CD45RA after IFNa exposure.

“Corroborating a priming toward lymphoid differentiation, HSCs exhibited an increased protein expression of CD38 and CD45RA after IFNa exposure ( Fig. 2e ).”

In a subset of the progenitor states, P53 and KRAS signaling were downregulated.

“In a subset of the progenitor states, P53 and KRAS signaling were downregulated ( Supplementary Table 6 ).”

The proportion of Pro-B cells in G2/M/S-phases demonstrated on average almost a 2-fold increase, compared to more modest increases in other lineages.

“Nonetheless, the proportion of Pro-B cells in G2/M/S-phases demonstrated on average almost a 2fold increase, compared to more modest increases in other lineages ( Fig. 2i) , consistent with the observed expansion of the lymphoid progenitors.”

Expression of IL1R1, TNFRSF1B and CXCL8 genes from the inflammatory response pathway were also downregulated.

“Expression of IL1R1 , TNFRSF1B and CXCL8 genes from the inflammatory response pathway were also downregulated ( Supplementary Table 6) .”

HSCs in the cell cycle did not express high CXCR4 gene expression.

“Indeed, HSCs expressing high levels of CXCR4 gene were less likely to be in cell cycle and enriched for baseline cells (P < 2.2 x 10 -22 , Fisher exact test) and conversely, HSCs in the cell cycle did not express high CXCR4 gene expression ( Supplementary Fig. 4a ).”

There was a downregulation of pro-inflammatory pathways, including the TNFa signaling via NFKB and inflammatory response pathways, across most of the progenitor subtypes but particularly in the cDCPs.

“Moreover, in contrast to the pro-inflammatory state of the IFNa-associated IGPs, we observed a downregulation of pro-inflammatory pathways, including the TNFa signaling via NFKB and inflammatory response pathways, across most of the progenitor subtypes but particularly in the cDCPs ( Fig. 2k-l, Supplementary Table 6) .”

The analysis confirmed upregulation of cell cycle-related pathways (G2M check point and E2F targets).

“The analysis also confirmed the upregulation cell cycle-related pathways (G2M check point and E2F targets) ( Fig. 2k, Supplementary Table 6 ).”

IFNa exerted strong transcriptional perturbations in the treated cells compared to baseline HSCs.

“we clustered cells from each individual separately based on the gene expression data and identified that IFNa exerted strong transcriptional perturbations in the treated cells compared to baseline HSCs ( Fig. 2a, Supplementary Fig. 3a ).”

RFX2 and RFX3 TFs were robustly upregulated in Cluster X compared to IMPs.

“We also observed a robust upregulation of RFX2 and RFX3 TFs, not well characterized in hematopoietic stem and progenitor cells ( Fig. 1e left, Supplementary Fig. 2d, Supplementary Table 3 ).”

Gene set enrichment analysis identified upregulation of the IFNa signaling pathway across the cell subsets.

“Next, to determine differentially regulated pathways, we performed gene set enrichment analysis using the canonical Hallmark gene sets in the IFNa-treated versus baseline cells and identified upregulation of the IFNa signaling pathway across the cell subsets as expected ( Fig. 2k, Supplementary Table 6 ).”

The inverse overlap, i.e. the overlap of IFNa-upregulated genes and genes downregulated in IGPs, was also observed (P = 1.73 x 10^-69, hypergeometric test).

“The inverse, i.e. the overlap of IFNa-upregulated genes and genes downregulated in IGPs, was also observed (P = 1.73 x 10 -69 , hypergeometric test, Supplementary Tables 3,6 ).”

IGPs were expanded upon IFNa treatment.

“we computed the proportion of stem and progenitor subsets within the CD34 + compartment and identified that the IGPs were indeed expanded upon IFNa treatment, consistent with the novel identification of this cell state ( Fig. 2b,c ).”

IFNa induces downregulation of TNFa and TGFb signaling.

“IFNa induces HSC proliferation and downregulation of TNFa and TGFb signaling.”

The frequency of myeloid cells in cell cycle was increased in the treated mutated versus wildtype progenitors.

“We found that the frequency of myeloid cells in cell cycle was increased in the treated mutated versus wildtype progenitors ( Fig. 3f, right ).”

The mutated cells were enriched in the MkPs at baseline.

“As we had previously demonstrated, the mutated cells were enriched in the MkPs at baseline ( Fig. 3b,c) .”

The lymphoid expansion was constrained in the mutated compartment, due to the relative expansion of the granulo-monocytic and megakaryocytic-erythroid progenitors compared to wildtype HSPCs.

“However, the lymphoid expansion was constrained in the mutated compartment, due to the relative expansion of the granulo-monocytic and megakaryocytic-erythroid progenitors compared to wildtype HSPCs ( Fig. 3d) .”

Accessibilities of the TWIST1 motif were enhanced after treatment.

“accessibilities of the TWIST1 motif were enhanced after treatment”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

Differential motif analysis revealed an upregulation of STAT2 and the proinflammatory REL of the NFKB complex.

“The differential motif analysis further revealed an upregulation of STAT2 and the proinflammatory REL of the NFKB complex”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

The additional insult to CALR activities in the double mutant clone induced an even greater UPR activation compared to single mutant HSCs.

“the additional insult to CALR activities in the double mutant clone induced an even greater UPR activation compared to single mutant HSCs”

GoT-ATAC identifies the same progenitor subsets identified in the GoT-IM data.

“GoT-ATAC identifies the same progenitor subsets identified in the GoT-IM data.”

At baseline, the double mutant clone remained subclonal to the dominant clone with the single canonical CALR mutation.

“At baseline, the double mutant clone remained subclonal to the dominant clone with the single canonical CALR mutation”

Integration of cells based on snATAC-seq data identified the same stem and progenitor cell relationships, including the similarity of the IGPs to the quiescent HSCs.

“we integrated the cells based the snATAC-seq data, and identified the same stem and progenitor cell relationships, including the similarity of the IGPs to the quiescent HSCs”

GoT-IM of baseline and IFNa treated samples reveal a novel cell state.

“GoT-IM of baseline and IFNa treated samples reveal a novel cell state.”

Cells from IFN04 harbored a single nucleotide variant M131I in the CALR allele trans to the MPN-causing frameshift mutation.

“cells from IFN04 harbored another mutation in CALR : a single nucleotide variant in the CALR allele (M131I, predicted to impact protein structure 61 ) which is trans to the MPN-causing frameshift mutation”

Transcription factors are upregulated in IGPs compared to IMPs.

“Dot plot showing expression levels of upregulated TFs in IGPs (vs. IMPs)”

In cDCPs, IFNa treatment downregulates TNFa signaling via NFKB.

“Pre-rank gene set enrichment analysis of DE genes before and after treatment with IFNa in cDCPs, showing downregulation of TNFa signaling via NFKB and the leading-edge genes.”

IFNa induces proliferation differentially in the mutated versus wildtype cells.

“IFNa induces proliferation differentially in the mutated versus wildtype cells.”

Transcription factors show motif enrichment and expression in IGPs relative to HSCs from IFNa-treated samples.

“Motif enrichment and expression of Transcription Factors (TF) in the IGPs relative to HSCs from IFNa-treated samples.”

IFNa induces lymphoid differentiation.

“IFNa induces lymphoid differentiation.”

Representative transcription factors are upregulated in inflammatory granulocytic progenitors (IGPs).

“UMAP showing expression levels of representative TF that are upregulated in IGPs.”

DE genes between IGPs and HSC1 are enriched in TNFa signaling via NFKB and G2M Checkpoint pathway.

“Genes highlighted in blue represent genes enriched in the TNFa signaling via NFKB and those in green enriched in G2M Checkpoint pathway”

IFNa induces HSC proliferation.

“IFNa induces HSC proliferation and downregulation of TNFa and TGFb signaling.”

The most significant regulatory peaks for RFX2 included motifs for PU.1, KLF, NR4A1/2 and AP-1 factors that were differentially expressed in the IGPs.

“the most significant regulatory peaks for RFX2 included motifs for PU.1, KLF, NR4A1/2 and AP-1 factors that were differentially expressed in the IGPs”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

A distal regulatory region with four negatively regulating loci was identified for HLA-DRA expression.

“We identified a distal regulatory region with four negatively regulating loci”

Unbiased clustering and dimensional reduction revealed that the double mutant clone at baseline clusters with the treated HSCs rather than with the other HSCs at baseline.

“unbiased clustering and dimensional reduction revealed that the double mutant clone at baseline clusters with the treated HSCs rather than with the other HSCs at baseline”

Overall, agnostic to the mutation status, IFNa-exposed myeloid progenitors demonstrated a trending increase of proliferation even in this non-paired cohort (P = 0.063, Wilcoxon rank sum).

“Overall, agnostic to the mutation status, IFNa-exposed myeloid progenitors demonstrated a trending increase of proliferation even in this non-paired cohort ( Supplementary Fig. 5c , P = 0.063, Wilcoxon rank sum).”

The double mutant HSCs intrinsically exhibited high IFN signaling at baseline.

“the double mutant HSCs intrinsically exhibited high IFN signaling at baseline”

IGPs were characterized by a robust upregulation of TF gene expression, especially those of AP-1 and RFX2/3.

“the IGPs were characterized by a robust upregulation of TF gene expression, especially those of AP-1 and RFX2/3”

At baseline, MPN stem cells show a skewing toward the myeloid lineages.

“At baseline, MPN stem cells show a skewing toward the myeloid lineages.”

Clonal HSCs with high IFNa signaling at baseline expand upon IFNa treatment.

“Clonal HSCs with high IFNa signaling at baseline expand upon IFNa treatment.”

Within the same negative regulatory region, an IGP-specific peak included the binding motif for RFX1-4, KLF factors and IRF1.

“within the same negative regulatory region, we identified an IGP-specific peak that included the binding motif for RFX1-4, KLF factors and IRF1”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

Clustering cells based on transcriptomic data identified the cell states identified by GoT-IM, including the novel IGP cell state.

“We clustered the cells based on the transcriptomic data and identified the cell states identified by GoT-IM, including the novel IGP cell state”

After treatment, there was an expansion of the lymphoid compartment in both wildtype and mutated cells.

“After treatment, we observed the expansion of the lymphoid compartment in both wildtype and mutated cells ( Fig. 3b,d) .”

IFNa boosted the proliferation of mutated HSCs to a greater degree than the wildtype counterparts.

“Intriguingly, IFNa boosted the proliferation of mutated HSCs to a greater degree than the wildtype counterparts ( Fig. 3e ), with a corresponding decrease in CXCR4 gene expression that was more pronounced in the mutated cells ( Supplementary Fig. 5b ).”

IFNa downregulated the motif accessibility of AP-1 TFs.

“IFNa downregulated the motif accessibility of AP-1 TFs”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

Differential TF motif enrichment analysis between IGPs and HSCs identified enhanced accessibility of the same TFs whose expression levels were elevated, including AP-1 family, CEBPB/D, IRF1 and RFX2/3.

“differential TF motif enrichment analysis between the IGPs and HSCs identified enhanced accessibility of the same TFs whose expression levels were elevated, including the motifs of the AP-1 family (FOS, JUN, JUND, JUNB, FOSL1, FOSL2), CEBPB/D, IRF1 and RFX2/3”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

Type 1-mutant reads and SNV-mutant reads in UMIs captured via GoT are mutually exclusive.

“Relative density of proportion of Type 1-mutant reads versus fraction of SNV-mutant reads in UMIs captured via GoT, showing mutual exclusivity.”

IFNa exerts strong transcriptional perturbations in HSPCs.

“IFNa exerts strong transcriptional perturbations in HSPCs.”

GoT-ATAC data confirmed the expansion of the lymphoid progenitors upon IFNa treatment.

“the GoT-ATAC data confirmed the expansion of the lymphoid progenitors upon IFNa treatment”

There was a corresponding decrease in CXCR4 gene expression that was more pronounced in the mutated cells.

“Intriguingly, IFNa boosted the proliferation of mutated HSCs to a greater degree than the wildtype counterparts ( Fig. 3e ), with a corresponding decrease in CXCR4 gene expression that was more pronounced in the mutated cells ( Supplementary Fig. 5b ).”

Enhanced chromatin accessibilities for small MAF factors (MAFK and MAFG) and their interacting partners NFE2L1/3 and BACH1/2 were observed in the IGPs.

“Enhanced chromatin accessibilities for small MAF factors (MAFK and MAFG) and their interacting partners NFE2L1/3 and BACH1/2 were also observed in the IGPs”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

Transcriptional similarity of IGPs to the most quiescent HSC1 population, especially with respect to the TF program, provides evidence for a novel route of granulocytic differentiation that bypasses the intermediate IMP states upon IFNa stimulation.

“Transcriptional similarity of IGPs to the most quiescent HSC1 population, especially with respect to the TF program, provides evidence for a novel route of granulocytic differentiation that bypasses the intermediate IMP states upon IFNa stimulation.”

The strong upregulation of RFX2/3 expression may be induced to rapidly downregulate MHC class II genes for granulocytic differentiation upon IFNa signaling.

“Thus, the strong upregulation of RFX2/3 expression may be induced to rapidly downregulate MCH class II genes for granulocytic differentiation upon IFNa signaling.”

The major shifts in progenitor output suggested that the clinical improvement in the patient's platelet count post-therapy (despite no significant reduction in the variant allele frequencies) may be due to the differentiation skewing away from the megakaryocytic lineage.

“The major shifts in progenitor output suggested that the clinical improvement in the patient's platelet count post-therapy (despite no significant reduction in the variant allele frequencies) may be due to the differentiation skewing away from the megakaryocytic lineage.”

IFNa may serve as another key mode of disease amelioration via downregulating MPN-associated inflammation.

“Our findings show that in human hematopoiesis, IFNa exerts an antiinflammatory response associated with a downregulation of TNFa signaling and therefore may serve as another key mode of disease amelioration via downregulating MPN-associated inflammation.”

Downregulation of NR4A1/2 relative to HSC1 is consistent with the upregulation of cell cycle-related genes in the IGPs.

“Their downregulation relative to HSC1 is therefore consistent with the upregulation of cell cycle-related genes in the IGPs ( Fig. 1h, Supplementary Table 3,4 ).”

In human hematopoiesis, IFNa exerts an anti-inflammatory response associated with a downregulation of TNFa signaling.

“Our findings show that in human hematopoiesis, IFNa exerts an antiinflammatory response associated with a downregulation of TNFa signaling and therefore may serve as another key mode of disease amelioration via downregulating MPN-associated inflammation.”

A novel model of re-balancing the differentiation landscape as a mode of therapeutic efficacy of IFNa is supported.

“Consistent with this hypothesis, the proportions of MEPs and MkPs in CD34 + cells could model the patient's platelet counts (P = 0.0071, F-test, Fig. 2g ), thus supporting a novel model of re-balancing the differentiation landscape as a mode of therapeutic efficacy of IFNa.”

These data indicated that IFNa can trigger opposing cell states within the same hematopoiesis.

“Altogether these data indicated that IFNa can trigger opposing cell states within the same hematopoiesis.”

IFNa may deplete clonal stem cells via induction of HSCs into cell cycle entry and exhaustion.

“IFNa remains a highly effective therapy for MPN, frequently resulting in the normalization of the patients' blood counts and even molecular response (i.e. reduction in variant allele frequencies), with evidence suggesting that IFNa may deplete clonal stem cells via induction of HSCs into cell cycle entry and exhaustion 12,18 .”

• cites [12] Rao, T. N. et al. JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality. Blood 137, 2139–2151 (2021). sourceNot checked — no full text of the source
• cites [18] Neurath, M. F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329–342 (2014). sourceNot checked — no full text of the source

The effects of IFNa on HSCs appear to be genotype-specific, as IFNa frequently induces molecular response in patients with JAK2-mutated MPN but not in those with CALR-mutated MPN.

“However, the effects of IFNa on HSCs appear to be genotypespecific as IFNa frequently induces molecular response in patients with JAK2 -mutated MPN but not in those with CALR -mutated MPN 19 .”

• cites [19] Vaidya, R. et al. Plasma cytokines in polycythemia vera: phenotypic correlates, prognostic relevance, and comparison with myelofibrosis. Am. J. Hematol. 87, 1003–1005 (2012). sourceNot checked — no full text of the source

JAK2-mutated MPN frequently displays clonal stem cell depletion upon IFNa treatment.

“while JAK2 -mutated MPN frequently displays clonal stem cell depletion upon IFNa treatment”

• cites [19] Vaidya, R. et al. Plasma cytokines in polycythemia vera: phenotypic correlates, prognostic relevance, and comparison with myelofibrosis. Am. J. Hematol. 87, 1003–1005 (2012). sourceNot checked — no full text of the source

IFNa differentially regulates mutated versus normal hematopoietic development.

“IFNa differentially regulates mutated vs. normal hematopoietic development.”

The predominant IFNa signaling signatures observed in IFNa-treated HSCs are largely direct rather than simply mediated by secondarily modulated cytokines.

“the predominant IFNa signaling signatures observed in IFNa-treated HSCs are largely direct rather than simply mediated by secondarily modulated cytokines”

IFNa treatment induces lymphoid differentiation.

“IFNa induces lymphoid differentiation and downregulation of TNFa and TGFb signaling.”

IFNa selects for HSC clones with high IFNa signaling at baseline.

“specifically suggesting that IFNa selects for HSC clones with high IFNa signaling at baseline”

PU.1 is the master regulator of IFNa-mediated remodeling of hematopoiesis.

“PU.1 is the master regulator of IFNa-mediated remodeling of hematopoiesis.”

The differential proliferation states as a function of the mutational status may contribute to the relative expansion of the myeloid versus lymphoid progenitors.

“Overall, these findings provide evidence that the differential proliferation states as a function of the mutational status may contribute to the relative expansion of the myeloid versus lymphoid progenitors.”

The UPR enhancement by CALR mutations is likely due to a heterozygous compromise of the critical chaperone protein encoded by CALR.

“likely due to a heterozygous compromise of the critical chaperone protein encoded by CALR”

The similarity of IGPs to quiescent HSCs provides evidence for a direct differentiation of IGPs from HSCs.

“again providing evidence for a direct differentiation of IGPs from HSCs”

HSCs with high expression of AP-1 and other immediate early response factors were primed toward a robust upregulation of RFX2/3 gene expression upon induction of IRF1 and PU.1 activities with IFNa treatment.

“These data further supported the model in which HSCs with high expression of the AP-1 and other immediate early response factors were primed toward a robust upregulation of RFX2/3 gene expression upon induction of IRF1 and PU.1 activities with IFNa treatment.”

IFNa induces PU.1 activity that regulates downstream differentiation activities.

“IFNa induces PU.1 activity that regulates downstream differentiation activities.”

There is a genotype-specific response to inflammation.

“indicating a genotypespecific response to inflammation”

IFNa exerts distinct phenotypic effects on HSPCs as a function of the mutation status in human.

“These findings provide direct evidence that IFNa exerts distinct phenotypic effects on HSPCs as a function of the mutation status in human.”

There is an unusually high concordance of gene expression of the TFs and their target motif accessibility, suggesting a rapid induction of the transcriptional regulatory program.

“These data thus demonstrated an unusually high concordance of gene expression of the TFs and their target motif accessibility, suggesting a rapid induction of the transcriptional regulatory program.”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

CALR-mutated MPN rarely demonstrates molecular response to IFNa.

“CALR -mutated MPN rarely demonstrates molecular response 19”

• cites [19] Vaidya, R. et al. Plasma cytokines in polycythemia vera: phenotypic correlates, prognostic relevance, and comparison with myelofibrosis. Am. J. Hematol. 87, 1003–1005 (2012). sourceNot checked — no full text of the source

RFX2/3 is a key TF in the overall regulatory network of IGPs.

“implicating RFX2/3 as key TFs in the overall regulatory network of IGPs”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.

The degree of cellular response to IFNa varies upon the degree of priming toward that signal at baseline.

“the degree of cellular response to IFNa varies upon the degree of priming toward that signal at baseline”

RFX2/3 is implicated in the upregulation of the AP-1 members upon IGP differentiation.

“implicating RFX2/3 in the upregulation of the AP-1 members upon IGP differentiation”

• AssumptionRests on an assumption: Chromatin accessibility of TF binding sites is a reliable surrogate of TF activity.