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Chronic myelogenous leukemia

β-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia

Abstract

Activation of nuclear β-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear β-catenin has a role in leukemia cell-intrinsic but not -extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, β-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples β-catenin expression from BCR-ABL1 kinase activity. In β-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of β-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic β-catenin levels, arguing against a role for β-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than β-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear β-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.

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Acknowledgements

We gratefully acknowledge Drs Michael Andreeff and Marina Konopleva (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) for providing the primary human MSCs that were used for these studies, as well as Jenny Ottley for clerical assistance. This work was supported by a Translational Research Program Award (6086-12 to MWD) and a Specialized Center of Research Program Award (GCNCR0314A-UTAH to MWD) from The Leukemia & Lymphoma Society (LLS), National Institutes of Health (NIH) P01CA049639 (to MWD), National Cancer Institute (NCI) R01CA178397 (to MWD and TO), NCI 5P30CA042014-24, and by the V Foundation for Cancer Research (to MWD and TO). AME was supported by a NCI T32CA093247, a Career Development Award from LLS (5090-12), and is currently funded through a Scholar Award from the American Society of Hematology (ASH). AME also acknowledges support from the NIH Loan Repayment Program. JSK is a Special Fellow of LLS and was supported by a Translational Research Training in Hematology Award from ASH.

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Correspondence to M W Deininger.

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MWD is a consultant for BMS, Novartis, ARIAD, Pfizer and Incyte. His laboratory receives research funding from BMS and Novartis.

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Eiring, A., Khorashad, J., Anderson, D. et al. β-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia 29, 2328–2337 (2015). https://doi.org/10.1038/leu.2015.196

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