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 plays 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.

Xiao-Ai-Ping inhibits proliferation and induces apoptosis of chronic myeloid leukemia cells through downregulating β-catenin signaling pathway

“…The current academic points of reasons leading to BCR-ABL kinaseindependent resistance are mainly focused on two aspects: activation of signaling pathways or extrinsic bone marrow (BM) microenvironmental conditions [42,43,45,52]. In addition, nuclear β-catenin leads to cells TKI resistance, but not BM-caused TKI resistance [45].…”

“…In contrast, Wnt/β-catenin signaling pathway was activated once, progenitor cells resume selfrenewal ability, further resulting in tumor development, recrudescence and drugs resistance [49][50][51]. The current academic points of reasons leading to BCR-ABL kinaseindependent resistance are mainly focused on two aspects: activation of signaling pathways or extrinsic bone marrow (BM) microenvironmental conditions [42,43,45,52]. In addition, nuclear β-catenin leads to cells TKI resistance, but not BM-caused TKI resistance [45].…”

“…It also plays a key role in self-renewal of HSCs, accelerating CML progression and inducing BCR-ABL kinase-independent resistance [32][33][34][35][36][37][38][39][40][41][42][43][44][45]. The controversies about the important roles of Wnt/β-catenin signaling pathway in aspect of LSCs self-renewal have been thoroughly introduced [46].…”

Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors

“…In this scenario, activation of alternative survival pathways must be responsible for primary or secondary resistance. Conceptually CML cell survival can be mediated through cell-autonomous (leukemia cell intrinsic) mechanisms or through cell-extrinsic microenvironmental factors provided by the bone marrow niche 55 . It is worth noting that while BCR-ABL1 independent resistance can confer overt resistance in active disease, it is also an important contributor to MRD, likely accounting for leukemia stem cell persistence despite DMR to TKI therapy.…”

“…Numerous other BCR-ABL1 independent factors have been proposed to contribute to CML LSC persistence and TKI resistance, including activation of SRC family kinases, Wnt-β-catenin, hypoxia-inducible factor 1α, arachidonate 15-lipoxygenase, miR-126, p53, MYC, ADAR1, SIRT1, RAD21 heat shock proteins, PP2A, Fap1, apoptotic regulators, the Hedgehog pathway and the IL-2/CD25 signaling circuit 55,70–95 . The number of theoretical synthetic lethality approaches involving TKIs and other inhibitors is destined to grow as new resistance mechanisms are unearthed, yet it remains unclear which combinations harbor clinical potential above and beyond TKI monotherapy.…”