ULK1 as a novel therapeutic target in Myeloproliferative Neoplasms
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE288528 | GEO | 2025/07/15
REPOSITORIES: GEO
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Project description:We provide evidence that genetic or pharmacological targeting of ULK1 delays disease progression in Jak2V617F-mutant MPN in vivo models. Mechanistically, the ULK1 anti-neoplastic effects were found to be associated, at least in part, with the transcriptional regulation of genes involved in myeloid malignancies and hematopoietic stem cell differentiation, leading to a reduced number of early-stage erythroid progenitors in both spleen and bone marrow, decreased levels of hemoglobin, hematocrit and red blood cells and spleen size in MPN in vivo models. These findings reveal a novel pro-tumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling characteristic of MPNs and highlight the potential of targeting this kinase as a new therapeutic strategy for MPN patients.
2025-07-15 | GSE288557 | GEO
Project description:Myeloproliferative neoplasms (MPNs) arise via the acquisition of a driver mutation in a single hematopoietic stem cell (HSC), often decades prior to the development of a clinical phenotype. The most common MPN driver mutation, JAK2V617F, activates aberrant JAK/STAT signaling via cytokine receptors critical for myelopoiesis. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production and contributes to lymphopenia in patients with MPNs and leades to elevated neutrophil-to-lymphocyte ratio (NLR), which is predictive of disease-related complications including thrombosis and mortality. We conducted this study to learn how hematopoiesis from the JAK2V617F clone affects lymphopoiesis in patients with MPNs. Although myeloid proliferation via aberrant JAK2 signaling is the most apparent mechanistic link between JAK2V617F and MPN phenotypes, our findings demonstrate that impaired lymphoid differentiation is an additional feature of JAK2V617F hematopoiesis, leading to the rarity of JAK2V617F lymphocytes despite the dominance of JAK2V617F HSCs in patients with MPNs. The combination of prolific myelopoiesis and defective lymphopoiesis from the JAK2V617F clone is a potential connection between MPN pathology and the surrogate markers, including NLR and lymphopenia, which hold prognostic significance. Based on our data, we speculate that, defective JAK2V617F lymphopoiesis and the consequent increased burden of lymphopoiesis from residual normal HSC clones drives the appearance of abnormal lymphocyte subsets, lymphoproliferative disease or T cell exhaustion in MPNs. Further study of MPN lymphopoiesis provides an opportunity to define the immune deficits underlying the myriad complications that affect patients with MPNs.
2024-09-01 | GSE269568 | GEO
Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-20 | GSE266848 | GEO
Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-02 | GSE266434 | GEO
Project description:Type I interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and can also directly inhibit tumor growth. IFN is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFN therapy and others do not. We have identified and characterized a novel pathway involving PKC upstream of the kinase ULK1. Engagement of the Type I IFN receptor triggers PKC-dependent phosphorylation of ULK1 on serines 341 and 495, required for subsequent engagement of p38 MAPK that regulates transcription of IFN-stimulated genes and subsequent growth inhibitory responses. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from patients with MPNs in vitro, while increased levels of ULK1 and p38 MAPK correlate with clinical response to IFN therapy in MPN patients. IFN treatment also induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vivo, triggering a negative feedback loop that suppresses IFN responses. Both ROCK homologs are overexpressed in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid progenitors from MPN patients. Together, our results identify activation of the PKC-ULK1-p38 MAPK cascade as a key and essential component for the IFN-response, regulated by a feedback loop involving ROCK1/2. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPN patients.
2022-01-10 | PXD021748 | Pride
Project description:Interferons (IFNs) are cytokines with potent anti-neoplastic properties and significant clinical activity in the treatment of myeloproliferative neoplasms (MPNs). The use of pegylated IFN for the treatment of MPNs has been of particular interest, with several clinical trials establishing clinical responses. Here we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B) is overexpressed in MPN patients. Targeted silencing of CHAF1B enhances transcription of IFN-stimulated genes and promotes IFN-dependent anti-neoplastic effects against MPN patient-derived cells. Our findings suggest that targeting CHAF1B in combination with IFN therapy may offer an avenue for the development of effective combination therapies for the treatment of MPNs.
2023-05-15 | PXD037376 | Pride
Project description:Gene expression profiles were established for 50 MPNs samples. RNA extracted from 2 healthy people was used as control. All MPNs were screened for JAK2V617F mutation as part of routine diagnostic practice.
2011-12-31 | E-MTAB-510 | biostudies-arrayexpress
Project description:Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation. Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele. While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients. This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles; however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617F abrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet2 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.
2022-05-25 | GSE203464 | GEO
Project description:Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets. CD45- CD31- Ter119- GFP+ cells were sorted from the BM of Nes-gfp;Mx1-cre;JAK2-V617F mice and control littermates 6 weeks after pIpC treatment and were subjected to RNA sequencing. Each sample was pooled from 3 animals of the same genotype.
2014-03-12 | E-GEOD-55798 | biostudies-arrayexpress
Project description:Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis compared to essential thrombocytosis (ET) or polycythemia vera (PV), the molecular distinctions between these subgroups are not well elucidated. We performed the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in PV, ET and PMF samples compared with healthy controls. We determined that PV and ET are characterized by aberrant promoter hypermethylation while PMF is an epigenetically distinct subgroup characterized by both aberrant hyper and hypomethylation. Aberrant hypomethylation in PMF was seen to occur in non CpG island loci, demonstrating further qualitative differences between the disease subgroups. The differentially methylated genes in PV and ET were involved predominantly in cell signaling pathways and were enriched for binding sites of GATA1 and other transcription factors. In contrast, aberrantly methylated genes in PMF were involved in inflammatory pathways and were enriched for NF1 (NFI), LEF1 and other transcription factors. Within the PMF subgroup, cases with ASXL1 disruptions formed an epigenetically distinct subgroup with relatively increased methylation. Cases of MPNs with TET2 mutations demonstrated decreased levels of hydroxymethylation and distinct set of hypermethylated genes. In contrast, the JAK2V617F mutation did not drive epigenetic clustering within MPNs. Finally, the significance of aberrant methylation was demonstrated by sensitivity of MPN derived cell lines to decitabine. These results demonstrate epigenetic differences between PMF and PV/ET and reveal methylomic signatures of ASXL1 and TET2 mutations. The study population consisted of 26 MPN patients (6 cases of ET, 8 cases of PV and 12 cases of PMF) and 3 healthy controls. Individual HpaII restriction digest profiles were compared to an internal MspI digest control, to yield differentially methylated fragments for every sample. The purpose of this study was to assess genome wide patterns of DNA methylation across the MPN stratified by disease class.
2012-12-05 | E-GEOD-42721 | biostudies-arrayexpress