Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pbx1 expression is required for myeloproliferative neoplasm onset and maintenance

ABSTRACT: Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiation of hematopoietic stem cells, and maintains proto-oncogenic transcriptional pathways implicated in several tumors. Its aberrant expression was found in a subset of myeloproliferative neoplasms (MPN) patients bearing the JAK2V617F mutation. To investigate if Pbx1 contributes to MPN, and to explore its potential as therapeutic target, we generated a new mouse strain, that we called JP, by crossing a known JAK2V617F inducible knock-in MPN model with a Pbx1 conditional-ko. In JP mice we can simultaneously activate the human JAK2 mutation and delete Pbx1. Typical MPN features, such as thrombocytemia and granulocytosis, did not develop in the absence of Pbx1. Erythrocytosis, initially displayed by JP mice, gradually resolved over time. Moreover, splenic myeloid metaplasia and in vitro cytokine independent growth were rescued by Pbx1 inactivation. Through RNA-Sequencing we analyzed molecular pathways downstream of Pbx1 and involved in MPN maintenance in stem and progenitor cells. The aberrant transcriptome in the MPN model compared to wild-type was rescued by the absence of Pbx1. Our results demonstrate that inhibition of the Pbx1-driven transcriptional program is beneficial in MPN. Modulation of Pbx1 activity by direct targeting or by targeting its downstream mediators might thus represent a novel therapeutic approach.

ORGANISM(S): Mus musculus

PROVIDER: GSE153482 | GEO | 2021/10/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Bone marrow erythroblast arrays

Project description:JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN), including polycythemia vera (PV), essential thrombocythemia (ET). We have demonstrated that heterozygous human JAK2V617F are associated with ET-like phenotypes while homozygosity for human JAK2V617F results in a striking phenotypic switch from an ET-like to PV-like phenotype. The resultant erythrocytosis is driven by increased numbers of erythroid progenitors and enhanced erythroblast proliferation. To establish the molecular mechanisms and pathways involved in the erythrocytosis, microarray was performed on bone marrow erythroblasts isolated from 8-10 weeks old homozygous, heterozygous mice and wildtype controls (3 mice for each genotype).

2014-03-26 | E-MTAB-2427 | biostudies-arrayexpress

Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm

Project description:The somatic JAK2V617F mutation is found in a majority of patients with myeloproliferative neoplasms (MPN). Chronic inflammation is often associated with MPN, but the role of inflammation in the pathogenesis of MPN remains elusive. Expression of interleukin-1 (IL-1), a key regulator of inflammation, is found elevated in MPN. Here, we show that increased IL-1β enhances myeloid cell expansion and promotes the development of bone marrow (BM) fibrosis in heterozygous Jak2V617F mouse model of MPN. Genetic deletion of IL-1 receptor 1 (IL-1R1) preferentially inhibited the expansion of Jak2 mutant hematopoietic stem/progenitor cells. Furthermore, IL-1R1 deletion or blockade with anti-IL-1R1 antibody significantly reduced leukocytosis and splenomegaly, and markedly inhibited BM fibrosis in homozygous Jak2V617F mutant mice. Collectively, our results suggest that IL-1 signaling plays an important role in progression to BM fibrosis in MPN, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.

2022-08-05 | GSE180339 | GEO

JAK2V617F Impairs Lymphoid Differentiation in Myeloproliferative Neoplasms

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

Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells

Project description:We report a Jak2V617F knock-in mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a selective competitive advantage over wild type HSCs. In contrast, myeloid progenitor populations are expanded and skewed towards the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F positive MPN. LKS cells were isolated from wild type (n=4) and JAK2V617F mutant mice (n=4). RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction and amplified using NUGEN amplification kit. cDNA was fragmented and biotinylated before hybridization onto Affymetrix Mouse Expression Array 430 2.0.

2010-05-28 | E-GEOD-21842 | biostudies-arrayexpress

Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis [HEL cell lines]

Project description:We used expression profiling, SNP arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients. MPN patients with homozygous JAK2V617F mutations were characterized by a distinctive transcriptional profile. Notably, a transcriptional signature consistent with activated JAK2 signaling is seen in all MPN patients regardless of clinical phenotype or mutational status. In addition, the activated JAK2 signature was present in patients with somatic CALR mutations. Conversely, we identified a gene expression signature of CALR mutations; this signature was significantly enriched in JAK2-mutant MPN patients consistent with a shared mechanism of transformation by JAK2 and CALR mutations. We also identified a transcriptional signature of TET2 mutations in MPN patent samples. Our data indicate that MPN patients, regardless of diagnosis or JAK mutational status are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis. [HEL cell lines] We have performed gene expression profiling in the JAK2V617F homozygous mutant HEL cell line following treatment with 2 independent shRNAs targeting JAK2 or 2 different control shRNAs

2014-06-03 | E-GEOD-54645 | biostudies-arrayexpress

Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells

2010-05-15 | GSE21842 | GEO

Quantitative Analysis of JAK2V617F/+ Plek2+/+ and JAK2V617F/+ Plek2-/- erythroblast and hematopoietic stem cells/ progenitor cells Transcriptomes

Project description:V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2V617F knockin mice. To reveal the role of Plek2 in the pathogenesis of JAK2V617F-induced MPNs and the detail mechanisms of its rescue, we performed RNA sequencing to analyze the gene expression profiles change between JAK2V617F/+ Plek2+/+ and JAK2V617F/+ Plek2-/- erythroblasts and hematopoietic stem/progenitor cells.

2019-04-11 | GSE97658 | GEO

Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis [MPN patients]

Project description:We used expression profiling, SNP arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients. MPN patients with homozygous JAK2V617F mutations were characterized by a distinctive transcriptional profile. Notably, a transcriptional signature consistent with activated JAK2 signaling is seen in all MPN patients regardless of clinical phenotype or mutational status. In addition, the activated JAK2 signature was present in patients with somatic CALR mutations. Conversely, we identified a gene expression signature of CALR mutations; this signature was significantly enriched in JAK2-mutant MPN patients consistent with a shared mechanism of transformation by JAK2 and CALR mutations. We also identified a transcriptional signature of TET2 mutations in MPN patent samples. Our data indicate that MPN patients, regardless of diagnosis or JAK mutational status are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis. [MPN patients] We have performed microarray gene expression analysis in 93 patients with MPNs (28 PV, 47 ET, 18 MF) and 11 age-matched normal donors.

2014-06-03 | E-GEOD-54644 | biostudies-arrayexpress

Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

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

Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

2024-05-20 | GSE266848 | GEO