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IKK-dependent activation of NF-?B contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1.

ABSTRACT: The product of the Ph chromosome, the BCR-ABL1 tyrosine kinase activates diverse signaling pathways in leukemic cells from patients with chronic myeloid leukemia (CML) and Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Previous studies showed that nuclear factor ?B (NF-?B) is activated in BCR-ABL1-expressing cells, but the mechanism of activation and importance of NF-?B to the pathogenesis of BCR-ABL1-positive myeloid and lymphoid leukemias are unknown. Coexpression of BCR-ABL1 and a superrepressor mutant of inhibitory NF-?B ? (I?B?SR) blocked nuclear p65/RelA expression and inhibited the proliferation of Ba/F3 cells and primary BCR-ABL1-transformed B lymphoblasts without affecting cell survival. In retroviral mouse models of CML and B-ALL, coexpression of I?B?SR attenuated leukemogenesis, prolonged survival, and reduced myeloid leukemic stem cells. Coexpression of dominant-negative mutants of I?B kinase ? (IKK?)/IKK1 or IKK?/IKK2 also inhibited lymphoid and myeloid leukemogenesis by BCR-ABL1. Blockade of NF-?B decreased expression of the NF-?B targets c-MYC and BCL-X and increased the sensitivity of BCR-ABL1-transformed lymphoblasts to ABL1 kinase inhibitors. These results demonstrate that NF-?B is activated through the canonical IKK pathway and plays distinct roles in the pathogenesis of myeloid and lymphoid leukemias induced by BCR-ABL1, validating NF-?B and IKKs as targets for therapy of Ph(+) leukemias.

SUBMITTER: Hsieh MY

PROVIDER: S-EPMC3983614 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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IKK-dependent activation of NF-κB contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1.

Hsieh Mo-Ying MY Van Etten Richard A RA

Blood 20140124 15

The product of the Ph chromosome, the BCR-ABL1 tyrosine kinase activates diverse signaling pathways in leukemic cells from patients with chronic myeloid leukemia (CML) and Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Previous studies showed that nuclear factor κB (NF-κB) is activated in BCR-ABL1-expressing cells, but the mechanism of activation and importance of NF-κB to the pathogenesis of BCR-ABL1-positive myeloid and lymphoid leukemias are unknown. Coexpression of BCR-ABL1 and a superre ...[more]

PMID: 24464015

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Project description:BackgroundThe BCR-ABL1 translocation occurs in chronic myeloid leukemia (CML) and in 25% of cases with acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKI) has fundamentally changed the treatment of CML. However, TKI are not equally effective for treating ALL. Furthermore, de novo or secondary TKI-resistance is a significant problem in CML. We screened a panel of BCR-ABL1 positive ALL and CML cell lines to find models for imatinib-resistance.ResultsFive of 19 BCR-ABL1 positive cell lines were resistant to imatinib-induced apoptosis (KCL-22, MHH-TALL1, NALM-1, SD-1, SUP-B15). None of the resistant cell lines carried mutations in the kinase domain of BCR-ABL1 and all showed resistance to second generation TKI, nilotinib or dasatinib. STAT5, ERK1/2 and the ribosomal S6 protein (RPS6) are BCR-ABL1 downstream effectors, and all three proteins are dephosphorylated by imatinib in sensitive cell lines. TKI-resistant phosphorylation of RPS6, but responsiveness as regards JAK/STAT5 and ERK1/2 signalling were characteristic for resistant cell lines. PI3K pathway inhibitors effected dephosphorylation of RPS6 in imatinib-resistant cell lines suggesting that an oncogene other than BCR-ABL1 might be responsible for activation of the PI3K/AKT1/mTOR pathway, which would explain the TKI resistance of these cells. We show that the TKI-resistant cell line KCL-22 carries a PI3K? E545G mutation, a site critical for the constitutive activation of the PI3K/AKT1 pathway. Apoptosis in TKI-resistant cells could be induced by inhibition of AKT1, but not of mTOR.ConclusionWe introduce five Philadelphia-chromosome positive cell lines as TKI-resistance models. None of these cell lines carries mutations in the kinase domain of BCR-ABL1 or other molecular aberrations previously indicted in the context of imatinib-resistance. These cell lines are unique as they dephosphorylate ERK1/2 and STAT5 after treatment with imatinib, while PI3K/AKT1/mTOR activity remains unaffected. Inhibition of AKT1 leads to apoptosis in the imatinib-resistant cell lines. In conclusion, Ph+ cell lines show a form of imatinib-resistance attributable to constitutive activation of the PI3K/AKT1 pathway. Mutations in PIK3CA, as observed in cell line KCL-22, or PI3K activating oncogenes may undelie TKI-resistance in these cell lines.

Dataset Information

IKK-dependent activation of NF-?B contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1.

Publications

IKK-dependent activation of NF-κB contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1.

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