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Expression data from loss-of-TET2 and/or JAK2V617F mutant Lineage-c-Kit+Sca-1+ (LSK) bone marrow cells

ABSTRACT: Recent studies have shown that both TET2 mutation and JAK2V617F mutation are frequent in myeloproliferative neoplasms patients. The pathophysiological roles of each mutation have been elucidated in murine models, but the cooperative effect of the two mutations has not been elucidated yet. In this study, we examined the function of the cooperative effect of loss-of-TET2 function and JAK2V617F mutation in murine hematopoiesis. In this study, we utilized wild type (WT) mice, TET2 knock down (TET2KD) mice, JAK2V617F transgenic mice, double mutant mice. We transplanted 4 types of E14.5 fetal liver cells (WT, TET2KD, JAK2V617F, double mutant) into lethally irradiated mice. At 10-16 weeks post-transplantation, LSK cells from the BM of the recipients were collected, and gene expression analysis was performed. (WT,5 mice at 16 weeks; TET2KD, 5 mice at 10 weeks; JAK2V617F, 5 mice at 16 weeks; double mutant, 5 mice at 13 weeks)

ORGANISM(S): Mus musculus

SUBMITTER: Takuro Kameda

PROVIDER: E-GEOD-62302 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from loss-of-TET2 and/or JAK2V617F mutant Lineage-c-Kit+Sca-1+ (LSK) bone marrow cells

Project description:Recent studies have shown that both TET2 mutation and JAK2V617F mutation are frequent in myeloproliferative neoplasms patients. The pathophysiological roles of each mutation have been elucidated in murine models, but the cooperative effect of the two mutations has not been elucidated yet. In this study, we examined the function of the cooperative effect of loss-of-TET2 function and JAK2V617F mutation in murine hematopoiesis.

2014-10-16 | GSE62302 | GEO

Mutation Order Affects Tumor Evolution and Clinical Course of Disease

Project description:Background: Cancers result from accumulation of somatic mutations and their properties are thought to reflect the sum of these mutations. However, little is known about the consequences of altering the order of mutation acquisition. Methods: Mutation order was determined in myeloproliferative neoplasm patients by genotyping hematopoietic colonies or next generation sequencing. Stem and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. Results: Age of presentation, acquisition of JAK2V617F homozygosity and the balance of immature progenitors were all influenced by mutation order. Compared to TET2-first patients, JAK2-first patients had an increased likelihood of presenting with polycythemia vera than essential thrombocythemia, an increased risk of thrombosis and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. In studies of single hematopoietic stem and progenitor cells (HSPCs), mutation order influenced the proliferative response to JAK2V617F and the capacity of double-mutant HSPCs to generate colony-forming cells. Moreover the HSPC compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2/TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2V617F in a cell-intrinsic manner, and prevented JAK2V617F from up-regulating genes associated with proliferation. These data demonstrate that mutation order influences progenitor proliferation and terminal cell expansion, thus influencing clinical presentation, thrombosis risk and progenitor response to targeted therapy. Conclusions: The order in which JAK2 and TET2 mutations are acquired influences clinical features, stem/progenitor cell biology and clonal evolution in patients with myeloproliferative neoplasms.

2014-11-17 | E-MTAB-3086 | biostudies-arrayexpress

RNA sequencing of LSK cells from mice with JAK2 mutation and HMGA2 expression

Project description:Either loss of EZH2 or redcuction of let-7 induces expression of HMGA2 and provokes severe myelofibrosis in mice carrying JAK2V617F. Therefore we compared gene expression profiles of LSK cells among WT mice, Hmga2-Tg mice, JAK2V617F-Tg mice, JAK2V617F/Hmga2 double-Tg mice, and JAK2V617F-Tg/EZH2 conditional KO mice.

2017-06-01 | GSE87464 | GEO

Gene expression profiling to study the transcriptional consequences of Jak2V617F expression and/or Tet2 loss in murine hematopoietic stem cells

Project description:To interrogate the molecular pathways disrupted by Jak2V617F expression and/or Tet2 loss, Lin-negative, Sca-1-positive, c-kit-positive (LSK) hematopoietic progenitor cells were isolated from bone marrow of wild-type, Jak2V617F, Tet2-null or Jak2V617F/Tet2-null animals (n= 2-4 mice per group) and subjected to gene expression profiling.

2014-10-31 | E-MTAB-2986 | biostudies-arrayexpress

Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

Project description:Mutations in the TET2 gene are frequent in myeloid disease, although their biological and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using ‘Next-Generation’ sequencing (NGS) for TET2 aberrations; 91 of whom were also subjected to SNP6 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) ≥10%, were identified in 39 of 320 (12%) MDS and 16 of 35 (46%) CMML patients (p<0.001). Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. ‘Deeper’ sequencing of 96 patient samples identified 4 additional mutations (RMA 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells in addition to CD34+ and total bone-marrow cells (23.5%, 38.5% and 43% RMA respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression or the JAK2V617F 46/1 haplotype between TET2-mutated and non-mutated patients. There was no significant prognostic association between TET2 mutations and WHO subtypes, IPSS score, cytogenetic status, or transformation to AML. On multivariate analysis, age (>50yrs) was associated with a higher incidence of TET2 mutation (p=0.02). Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from bone marrow or peripheral blood samples. Copy number and acquired UPD analysis of Affymetrix SNP 6.0 arrays was performed for 91 cases with Myelodysplastic syndromes.

2010-07-30 | E-GEOD-23300 | biostudies-arrayexpress

JAK2V617F mutation in CD34+ stem cells of essential thrombocythemia

Project description:The JAK2V617F mutation has been reported in about 40-60% of Essential Thrombocythemia (ET) patients. However, little is known about specific molecular abnormalities of the hematopoietic stem cell compartment of ET according to JAK2 mutation. Therefore, we compared the gene expression profiles of bone marrow (BM) CD34+ cells from 16 patients with and without the JAK2V617F mutation to identify differentially expressed genes. Keywords: cell type comparison Sample name and JAK2V617F mutation: - BM CD34+ cells from healthy subject (CTR) - ET JAK2V617F-positive: ET 1, ET 4, ET 6, ET 7, ET 8, ET 10, ET 12, ET 15 - ET JAK2V617F-negative: ET 2, ET 3, ET 5, ET 9, ET 11, ET 13, ET 14, ET 16

2010-04-06 | E-GEOD-9827 | biostudies-arrayexpress

DNMT3A and TET2 Compete and Cooperate to Repress Differentiation Lineage-Specific Factors in Hematopoietic Stem Cells

Project description:Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation-hydroxymethylation pathway. Using double knock-out (DKO) mice in which malignancy development is accelerated, we show that the DKO methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulator Klf1 is upregulated in DKO HSCs. DNMT3A and TET2 both repress Klf1 suggesting a model of cooperative inhibition by the epigenetic modifiers. These data demonstrate a dual role for TET2 in promoting and inhibiting HSC differentiation, loss of which, along with DNMT3A, obstructs differentiation leading to transformation.

2016-05-20 | GSE72148 | GEO

Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

2010-07-30 | GSE23300 | GEO

JAK2V617F mutation in CD34+ stem cells of essential thrombocythemia

2010-04-06 | GSE9827 | GEO

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

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