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

Autor: Eiring AM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Khorashad JS; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Anderson DJ; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Yu F; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.; Beijing Tsinghua Chang Gung Hospital, Tsinghua University, Beijing, China., Redwine HM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Mason CC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Reynolds KR; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Clair PM; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Gantz KC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Zhang TY; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Pomicter AD; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Kraft IL; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Bowler AD; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Johnson K; Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA., Partlin MM; Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA., O'Hare T; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.; Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA., Deininger MW; Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.; Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2015 Dec; Vol. 29 (12), pp. 2328-37. Date of Electronic Publication: 2015 Jul 23.
DOI: 10.1038/leu.2015.196
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: