Single-cell gene expression profiling (sc-RNA-seq) of CD34+ hematopoietic stem cells from Myeloproliferative Neoplasm (MPN) patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190383 | GEO | 2023/01/31
REPOSITORIES: GEO
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Project description:Genomic DNA of granulocytes or mononuclear cell fractions of 408 myeloproliferative neoplasm (MPN) patients was analyzed using Affymetrix Genome-Wide Human SNP 6.0 arrays
2011-07-01 | E-MTAB-608 | biostudies-arrayexpress
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
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
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.
2014-06-03 | GSE54644 | GEO
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
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE197942 | GEO
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE189569 | GEO
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE189568 | GEO
Project description:Myeloproliferative neoplasms (MPN) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although actionable mechanisms driving progression remain elusive. The HMGA1 chromatin regulator is up-regulated during MPN progression with highest levels after transformation. HMGA1 depletion in JAK2V617F MPN AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F transgenic mice, decreasing blood counts and expansion in stem and myeloid progenitors while preventing splenomegaly and fibrosis within the spleen and bone marrow. RNA sequencing revealed HMGA1-dependent transcriptional networks that govern proliferation (E2F, G2M, mitosis, MYC targets) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates phenotypes observed with HMGA1 depletion whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including GATA2, are activated in human MF after leukemic transformation. Further, HMGA1 depletion synergizes with the JAK2 inhibitor, ruxolitinib, to prolong survival in murine MPN AML. These findings illuminate HMGA1 as a key epigenetic switch required for MPN transformation and promising therapeutic target to treat or prevent disease progression.
2023-10-05 | GSE183374 | GEO
Project description: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.
2021-10-21 | GSE153482 | GEO