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CXCL8/CXCR2 signaling is Enriched in Fibrotic Myeloproliferative Neoplasms and is Vulnerable to Therapeutic Inhibition [ATAC-Seq]

ABSTRACT: Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-kB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189978 | GEO | 2023/05/12

REPOSITORIES: GEO

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CXCL8/CXCR2 signaling is Enriched in Fibrotic Myeloproliferative Neoplasms and is Vulnerable to Therapeutic Inhibition [RNA-Seq]

Project description:Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-kB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

2023-05-12 | GSE189979 | GEO

IL-13/IL-4 signaling contributes to fibrotic progression of the myeloproliferative neoplasms

Project description:Myelofibrosis (MF) is a disease with high unmet medical need since bone marrow transplant is not an option for many patients and JAK inhibitors are generally effective for only 2-3 years. MF is characterized by the presence of dysplastic megakaryocytes and progression to fulminant disease is associated with significantly increased fibrosis in the bone marrow. Despite evidence of an inflammatory state in MF that drives disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after development of fibrosis coupled with analysis of bone marrow populations by scRNA-seq. We found high IL-13 levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced the surface expression of TGF-B and collagen biosynthesis. Analysis of samples from patients with myelofibrosis revealed elevated levels of IL-13 in plasma and increased IL-13 receptor expression in megakaryocytes in the bone marrow, indicating that our observations in mice are relevant in human disease. In vivo, IL-13 overexpression promoted disease progression while reducing IL-13/IL-4 signaling reduced several features of the disease including fibrosis. Lastly, we found an increase in T cells and mast cells, which are known sources of IL-13 in MF bone marrow. Together, our data demonstrate that IL-13 is involved in the progression of MF and that inhibition of the IL-13/IL-4 signaling pathway should be investigated as a therapeutic option in MF.

2023-01-03 | GSE205884 | GEO

Effect of IL13 on MPLW515L Megakaryocytes

Project description:Myelofibrosis (MF) is a disease associated with high unmet medical needs since allogeneic stem cell transplantation is not an option for most patients and JAK inhibitors are generally effective for only 2-3 years and do not delay disease progression. MF is characterized by the presence of dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence of an inflammatory milieu in MF that contributes to disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after development of fibrosis coupled with analysis of bone marrow populations by scRNA-seq. We found high IL-13 levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced the surface expression of TGF- and collagen biosynthesis. Analysis of samples from patients with myelofibrosis similarly revealed elevated levels of IL-13 in plasma and increased IL-13 receptor expression by marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression while reducing IL-13/IL-4 signaling reduced several features of the disease including fibrosis. Lastly, we found an increase in the numbers of marrow T cells and mast cells, which are known sources of IL-13. Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.

2022-07-10 | GSE207691 | GEO

Identification of potential of new therapeutic approaches for JAK2 V617F mutant patients

Project description:n patients with PMF, excessive secretion of inflammatory cytokines results in fibrotic changes in bone marrow and diminishes the quality of life of the affected patients due to systemic symptoms long-term ruxolitinib therapy may reverse or markedly delay BM fibrosis progression in advanced MF suggests kavasincha 2018

2023-05-18 | PXD027250 | Pride

Effects of Pim1 inhibition with TP-3654 on hematopoietic progenitors of Jak2V617F mice

Project description:Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. So, we investigated the role of Pim1 in myelofibrosis. 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, 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. 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.

2022-07-01 | GSE183467 | GEO

MYC-Alarmin Axis as a Novel Therapeutic Vulnerability in Triple Negative Myeloproliferative Neoplasms

Project description:Despite advances in our understanding of the underlying genetic abnormalities in myelofibrosis (MF) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly in triple negative MF patients who lack mutations in the JAK2 kinase pathway. Here we report that MYC copy number gain (e.g., trisomy 8) is frequently identified in triple negative MF where MF development and progression rely on MYC-directed activation of S100A9, a Danger Associated Molecular Pattern (DAMP) protein that plays pivotal roles in inflammation. Notably, MYC-S100A9 axis underlies complex network of inflammatory signaling that involves various hematopoietic cell types in the bone marrow microenvironment. Accordingly, small molecules targeting the MYC-S100A9 pathway effectively ameliorated the MF phenotypes, highlighting MYC-alarmin axis as a novel therapeutic vulnerability in a subgroup of MF patients.

2024-04-29 | GSE240963 | GEO

Inhibition of CDK6 using Palbociclib in combination with Ruxolitinib markedly improves myelofibrosis in murine models

Project description:Myelofibrosis (MF) is a deadly blood neoplasia that presents the worst prognosis among myeloproliferative neoplasms (MPN). Expression of CDK6 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 of Palbociclib alone significantly reduced leukocytosis, 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. Mechanistically, we show that Palbociclib treatment or depletion of CDK6 inhibits Aurora kinase, NF-κB and TGF-β signaling pathways in Jak2V617F mutant hematopoietic cells. Overall, our data suggest that Palbociclib in combination with Ruxolitinib may have therapeutic potential for treatment of MF.

2021-11-05 | GSE173814 | GEO

Epigenetic Therapy Increases Therapeutic Efficacy in Myeloproliferative Neoplasms Through Inhibition of Aberrant Inflammatory Signaling

Project description:The mechanisms that mediate transformation in MPN are not fully delineated and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify Nfb signaling as a key pathway activated in malignant and non-malignant cells in MPN. Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor kB (NF-kB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-kB signaling and reduced cytokine production in vivo. Most importantly, combined JAK/BET inhibition resulted in a marked reduction in the serum levels of inflammatory cytokines, reduced disease burden, and reversed bone marrow fibrosis in vivo.

2017-12-14 | GSE91062 | GEO

Longitudinal inflammatory gene expression associated with advanced myelofibrosis

Project description:Myelofibrosis (MF) is a progressive, bone marrow (BM) malignancy associated with monocytosis, and is believed to promote the pathological remodelling of the extracellular matrix. Here, we show that the pathologic grading of MF was associated with inflammatory gene expression in primary patient samples.

2022-07-11 | GSE206770 | GEO

Inflammatory gene expression associated with advanced myelofibrosis

2022-07-11 | GSE206768 | GEO

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