Publications
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Interleukin-1 (IL-1); Nature Communications 2022
Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm
https://www.nature.com/articles/s41467-022-32928-3
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Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1β enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.
PIM1_TP-3654; Leukemia 2021
Genetic ablation of Pim1 or pharmacologic inhibition with TP-3654 ameliorates myelofibrosis in murine model
https://www.nature.com/articles/s41375-021-01464-2
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Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). The JAK inhibitor Ruxolitinib can reduce constitutional symptoms but it does not substantially improve bone marrow fibrosis. Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. Here, we show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis and splenomegaly, and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, we show that TP-3654 treatment significantly inhibits mTORC1, MYC and TGF-β signaling in Jak2V617F mutant hematopoietic cells and diminishes the expression of fibrotic markers in the bone marrow. Collectively, our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF.
CDK6_Palbociclib; Cancer Research 2021
CDK6 is a therapeutic target in myelofibrosis
https://cancerres.aacrjournals.org/content/81/16/4332
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Myelofibrosis (MF) is a deadly blood neoplasia with the worst prognosis among myeloproliferative neoplasms (MPN). The JAK2 inhibitors Ruxolitinib and Fedratinib have been approved for treatment of MF, but they do not offer significant improvement of bone marrow fibrosis. CDK6 expression is significantly elevated in MPN/MF hematopoietic progenitor cells. In this study, we investigated the efficacy of CDK4/6 inhibitor Palbociclib alone or in combination with Ruxolitinib in Jak2V617F and MPLW515L murine models of MF. Treatment with Palbociclib alone significantly reduced leukocytosis and splenomegaly and inhibited bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of Palbociclib and Ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size, and abrogation of bone marrow fibrosis in murine models of MF. Palbociclib treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, treatment with Palbociclib or depletion of CDK6 inhibited Aurora kinase, NF-κB, and TGF-β signaling pathways in Jak2V617F mutant hematopoietic cells and attenuated expression of fibrotic markers in the bone marrow. Overall, these data suggest that Palbociclib in combination with Ruxolitinib may have therapeutic potential for treatment of MF and support the clinical investigation of this drug combination in patients with MF.
U2AF1; Leukemia 2021
U2af1 is required for survival and function of hematopoietic stem/progenitor cells
https://www.nature.com/articles/s41375-020-01116-x
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U2AF1 is involved in the recognition of the 3′ splice site during pre-mRNA splicing. Mutations in U2AF1 are frequently observed in myelodysplastic syndromes. However, the role of wild-type U2AF1 in normal hematopoiesis has remained elusive. Using a novel conditional U2af1 knockout allele, we have found that deletion of U2af1 results in profound defects in hematopoiesis characterized by pancytopenia, ablation of hematopoietic stem/progenitor cells (HSPC) leading to bone marrow failure and early lethality in mice. U2af1 deletion impairs HSPC function and repopulation capacity. U2af1 deletion also causes increased DNA damage and reduced survival in hematopoietic progenitors. RNA sequencing analysis reveals significant alterations in the expression of genes related to HSC maintenance, cell proliferation, and DNA damage response-related pathways in U2af1-deficient HSPC. U2af1 deficiency also induces splicing alterations in genes important for HSPC function. This includes altered splicing and perturbed expression of Nfya and Pbx1 transcription factors in U2af1-deficient HSPC. Collectively, these results suggest an important role for U2af1 in the maintenance and function of HSPC in normal hematopoiesis. A better understanding of the normal function of U2AF1 in hematopoiesis is important for development of appropriate therapeutic approaches for U2AF1 mutant induced hematologic malignancies.
HMGA2; Blood 2017
Hmga2 promotes the development of myelofibrosis in Jak2V617F knock-in mice by enhancing TGF-β1 and Cxcl12 pathways
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Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in ∼50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2V617F knockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF in mice expressing Jak2V617F Mechanistically, the data show that expression of Hmga2 enhances the activation of transforming growth factor-β1 (TGF-β1) and Cxcl12 pathways in mice expressing Jak2V617F In addition, expression of Hmga2 causes upregulation of Fzd2, Ifi27l2a, and TGF-β receptor 2. Forced expression of Cxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bone marrow of Jak2V617F mice, whereas TGF-β1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2V617F in the pathogenesis of MF.
STAT3 in LGL; British Journal of Hematology 2016
STAT3Â mutations are not sufficient to induce large granular lymphocytic leukaemia in mice
New insights into TCR β-selection; Trends in Immunology 2021
https://www.sciencedirect.com/science/article/pii/S1471490621001198?via%3Dihub
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T cell receptor (TCR) β-selection (herein referred to as β-selection) is a pivotal checkpoint in mammalian T cell development when immature CD4–CD8– T-cells (thymocytes) express pre-TCR following successful Tcrb gene rearrangement. At this stage, αβ T cell lineage commitment and allelic exclusion to restrict one β-chain per cell take place and thymocytes undergo a proliferative burst. β-selection is known to be crucially dependent upon synchronized Notch and pre-TCR signaling; however, other necessary inputs have been identified over the past decade, expanding our knowledge and understanding of the β-selection process. In this review, we discuss recent mechanistic findings that have enabled a more detailed decoding of the molecular dynamics of the β-selection checkpoint and have helped to elucidate its role in early T cell development.
New Insights into Epigenetic Regulation of T Cell Differentiation; Cells 2021
https://www.mdpi.com/2073-4409/10/12/3459
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Immature CD4− CD8− thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4+ (helper) or CD8+ (cytotoxic) T cells. Activation of naïve CD4+ and CD8+ T cells in the presence of specific cytokines results in the induction of transcriptional programs that result in their differentiation into effector or memory cells and in the case of CD4+ T cells, the adoption of distinct T-helper fates. Previous studies have shown that histone modification and DNA methylation play important roles in each of these events. More recently, the roles of specific epigenetic regulators in T cell differentiation have been clarified. The identification of the epigenetic modifications and modifiers that control mature T cell differentiation and specification has also provided further insights into how dysregulation of these processes can lead to cancer or autoimmune diseases. In this review, we summarize recent findings that have provided new insights into epigenetic regulation of T cell differentiation in both mice and humans.
Epigenetic Regulation of T Cell Development; Int Rev Immunology 2021
https://www.tandfonline.com/doi/full/10.1080/08830185.2021.2022661
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Epigenetic regulators are pivotal factors that influence and control T cell development. Recent findings continue to reveal additional elements of epigenetic modifications that play significant and crucial roles at different stages of T cell development. Through gaining a better understanding of the various epigenetic factors that influence the formation and survival of maturing T cells, new therapies can potentially be developed to combat diseases caused by dysregulated epigenetic chromatin modifications. In this review, we summarize the recent studies which shed light on the epigenetic regulation of T cell development especially at the critical stage of β-selection.