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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61696 | GEO | 2015/06/18

SECONDARY ACCESSION(S): PRJNA261873

REPOSITORIES: GEO

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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

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

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

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

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JAK2 inhibition in Philadelphia chromosome like acute lymphoblastic leukemia

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HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias.

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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.

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Comparative gene expression profiling of MHH-CALL4 cells subject to pharmacological JAK2 inhibitor treatment (ruxolitinib or CHZ868) or shRNA-mediated JAK2 depletion in vitro

Project description:Gene expression profiling was performed to characterise transcriptional programs associated with response to type I JAK2 inhibitor ruxolitinib, type II JAK2 inhibitor CHZ868 or shRNA-mediated JAK2 knockdown in MHH-CALL4 cells.

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

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

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