title: 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.
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Khorashad
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.|Beijing Tsinghua Chang Gung Hospital, Tsinghua University, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Yu
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Redwine
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Mason
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Reynolds
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Clair
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Gantz
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: T Y
authors.initials: TY
authors.lastname: Zhang
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Pomicter
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: I L
authors.initials: IL
authors.lastname: Kraft
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Bowler
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: K
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: M Mac
authors.initials: MM
authors.lastname: Partlin
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: 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.
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D015820:Cadherins / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000502:physiology*
chemical_list: C581634:BCR-ABL1 fusion protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl