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JAK2 inhibition in Philadelphia chromosome like acute lymphoblastic leukemia

ABSTRACT: CRLF2 rearranged Ph-like ALL cells are driven by oncogenic cytokine receptor signaling mediated by CRLF2 and JAK2. MHH-cALL4 cells were treated with ruxolotinib (JAK2 inhibitor) to provide insight into mechanisms of drug resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132486 | GEO | 2020/05/28

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.

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JAK2 inhibition in Philadelphia chromosome like acute lymphoblastic leukemia

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The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.

Project description:We studied the in vitro and in vivo efficacy of the HDAC inhibitor Givinostat/ITF2357 in BCP-ALL with CRLF2 rearrangements. We used BCP-ALL CRLF2- rearranged MHH-CALL4 and MUTZ5 cell lines as well as blasts from CRLF2 rearranged BCP-ALL patients and patients’ derived xenograft samples. We conclude that Givinostat may represent a novel and effective tool, in combination with current chemotherapy, to treat this subsets of ALL with poor prognosis and chemotherapy-related toxicity.

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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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RNA-seq of human leukemia cell lines, MHH-CALL-4 and MUTZ-5, treated either with Ruxolitinib, FX1, or their combination.

Project description:CRLF2-rearranged acute lymphoblastic leukemia (ALL) is associated with poor clinical outcomes. Although JAK1/2 is activated in this type of ALL, treatment with JAK1/2 inhibitors is insufficient in inhibiting cell growth and inducing apoptosis. BCL6 upregulation upon JAK inhibition may account for this insufficiency. Therefore, we compared gene expression changes of two CRLF2-rearranged ALL cell lines, MHH-CALL-4 and MUTZ-5, treated with either ruxolitinib(a JAK1/2 inhibitor), FX1(a BCL6 inhibitor), their combination, or control.

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Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we analyzed the gene expression changes after treatment with Imatinib or Imatinib + RI-BPI. Three Ph+ ALL cell lines (BV-173, SUP-B15 and TOM-1) were treated in the presence or absence of 10 μM STI571 (Imatinib) or in the presence of both 10 μM STI571 and 20 μM RI-BPI for 24 hours.

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Effect of imatinib on philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment.

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Transcriptome Analysis of treated cells in Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia

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Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia

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Ph-like acute lymphoblastic leukemia in adults is characterized by IgH-CRFL2 and JAK2 mutations and poor prognosis [HG-U133B]

Project description:Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Among 207 adult B-cell precursor ALL patients, 26 (13%) were classified as Ph-like using Affymetrix microarrays. The incidence of this subtype was 25% among 105 B-cell precursor ALL patients negative for BCR-ABL1 and MLL-translocations (B-other). All patients with IgH-CRLF2 translocation (38% vs 0%; p=0.002) or mutations in JAK2 (44% vs. 0%; p<0.001) were exclusively found in the Ph-like subgroup. Clinical and outcome analyses were restricted to patients treated within GMALL trials 06/99 and 07/03 (n=107). The complete remission (CR) rate after induction was 100% for Ph-like (n=19) and B-other patients (n=40). After induction, significantly fewer Ph-like patients reached molecular CR (33% vs 79%; p=0.01). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous CR (24% vs 62%; p<0.001) and overall survival (22% vs 64%; p=0.006) compared to B-other ALL patients. Subsequent analysis led to a clinically applicable algorithm identifying this patient subset with a specificity of 100%. Our study is the first to demonstrate that the profile of genetic events in adult Ph-like ALL resembles pediatric Ph-like ALL and differs from B-other ALL. The Ph-like phenotype associates with inferior outcomes in intensively treated adult ALL patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.

2017-02-28 | GSE66005 | GEO

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