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JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias

ABSTRACT: JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias

PROVIDER: PRJNA397978 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5927340_1.fastq.gz	Fastqsanger.gz
	SRR5927340_2.fastq.gz	Fastqsanger.gz
	SRR5927350_1.fastq.gz	Fastqsanger.gz
	SRR5927350_2.fastq.gz	Fastqsanger.gz
	SRR5927360.fastq.gz	Fastqsanger.gz

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JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias.

Project description:Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.

| S-EPMC6049517 | biostudies-literature

Comparison of the transcriptome of TEL-JAK2- versus activated NOTCH1 (ICN1)-induced T cell acute lymphoblastic leukemias (mouse)

2013-09-28 | GSE51243 | GEO

Comparison of the transcriptome of TEL-JAK2- versus activated NOTCH1 (ICN1)-induced T cell acute lymphoblastic leukemias (mouse)

Project description:The TEL-JAK2 fusion oncogene and the ICN1 activated allele of NOTCH1 are the result of specific chromosomal translocations in T cell acute lymphoblastic leukemia (T-ALL). Mouse models of these diseases (TEL-JAK2 transgenic mice; Carron C. et al. Blood (2000); a bone marrow transplantation model for ICN1-induced T-ALL) were used to compare the transcriptional program specific to each oncoprotein in mouse models of these leukemias. Tumor load was >50% leukemic cells in all selected organs. Leukemic cells were collected from the thymus of terminally-ill TEL-JAK2 leukemic mice and bone marrow of terminally-ill ICN1 leukemic mice. RNA was extracted from each sample and processed for hybridization to Affymetrix arrays.

2013-09-28 | E-GEOD-51243 | biostudies-arrayexpress

Lmo2 is dispensable for maintenance of most Lmo2-induced murine T-cell leukemias

Project description:Lmo2 is an oncogenic transcription factor that is a frequent target of chromosomal abnormalities in this T-cell acute lymphoblastic leukemia (T-ALL). In transgenic mouse models, overexpression of Lmo2 causes thymocyte self-renewal leading to T-cell leukemia with long latency. However, the requirement of Lmo2 for maintenance of overt leukemia is poorly understood. We found that Lyl1, a critical cofactor for Lmo2-induced leukemia, is frequently lost in cell lines derived from Lmo2-transgenic mice, raising the possibility that Lmo2 function is dispensable at this stage. To study this, we developed a Tetracycline-repressible knock-in mouse model (Vav-TRE-Lmo2), which expresses Lmo2 throughout the haematopoietic system. This led to specific effects on T-cell development and the development of T-cell leukemia with long latency, preceded by the presence of self-renewing T-cells in the thymus. Repression of Lmo2 overcame the Lmo2-induced thymocyte developmental block at the preleukemic stage and led to elimination of Lmo2-induced thymocyte self-renewal in vivo. In contrast, Lmo2 function was dispensable for the majority of overt Lmo2-induced T-cell leukemias as well as leukemia-derived cell lines, implying an evolution of oncogene addiction in the majority of T-cell leukemias. Lmo2-dependence in T-ALL was associated with an immature gene expression profile, but could not be predicted by immunophenotype or assessment of Notch pathway activation. Thus, Lmo2 can give rise to both Lmo2-depenent and –independent T-cell leukemias. The Vav-TRE-Lmo2 model should be useful to determine the molecular features associated with Lmo2-dependence, as well as the critical components of the Lmo2-induced self-renewal pathways in T-ALL.

2022-01-01 | GSE125674 | GEO

Lmo2 is dispensable for maintenance of most Lmo2-induced murine T-cell leukemias

Project description:Lmo2 is dispensable for maintenance of most Lmo2-induced murine T-cell leukemias

| PRJNA517144 | ENA

JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-05-31 | GSE102535 | GEO

Type II JAK2 Inhibitor NVP-CHZ868 is Active in Vitro and in Vivo Against JAK2-Dependent B-cell Acute Lymphoblastic Leukemias

Project description:Gene expression profiling was performed to define transcriptional programs associated with response to type II JAK2 inhibitor NVP-CHZ868 alone or in combination with dexamethasone in vitro and in vivo. MHH-CALL4 cells harboring a CRLF2 rearrangement and JAK2 I682F mutation were treated with vehicle, CHZ868, dexamethasone, or CHZ868 + dexamethasone combination for 12 hours in triplicate. RNA was then extracted for hybridization on Affymetrix microarrays. CRLF2+ patient-derived xenografts (05-412, 05-440, and 05-537) were treated in vivo for 3 days with vehicle, CHZ868, dexamethasone, or CHZ868 + dexmathasone combination for 3 days and then sacrificed. Transcriptional profiling was performed on unselected splenocytes from these animals.

2015-06-18 | E-GEOD-61696 | biostudies-arrayexpress

The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia

Project description:PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream STATs in an apparently non-canonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and, therefore, possessing transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the JAK-STAT signaling cascade, and thus, by interfering with these two important pathways, may promote leukemogenesis.

2014-12-29 | GSE56449 | GEO

Type II JAK2 Inhibitor NVP-CHZ868 is Active in Vitro and in Vivo Against JAK2-Dependent B-cell Acute Lymphoblastic Leukemias

2015-06-18 | GSE61696 | GEO

JAK2 inhibition in Philadelphia chromosome like acute lymphoblastic leukemia

Project description:JAK2 inhibition in Philadelphia chromosome like acute lymphoblastic leukemia

| PRJNA548171 | ENA