Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance

Abstract

Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 was noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provides preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment. [Mol Cancer Ther 2008;7(10):3169 -75]

JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

“…40 It will be of interest to study whether and how STAT3 induces TKI resistance as STAT3 can compensate for STAT5 under certain circumstances, and there is preliminary evidence to implicate STAT3 in drug resistance in CML. 41,42 JAK2: a promising candidate in CML therapy?…”

“…102 Similarly, K562 cells become resistant to BCR-ABL1 TKIs when cultured in bone marrow stroma-derived conditioned medium (CM), highlighting the importance of the microenvironment. 41 Stroma-induced drug resistance correlates with increased pSTAT3 levels. 41 Reducing the expression of JAK2 and TYK2 by siRNA or inhibiting JAK kinase activity by INCB-018424 blocked CMmediated STAT3 activation and sensitized CML cells to nilotinibmediated cell death.…”

Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt–β-catenin signaling

“…49 Previous studies have suggested a potential role for the tumor microenvironment in protecting leukemia cells from the effects of drug therapy. 14,18,19,50 However, it has been unclear whether such interactions could determine resistance of human CML LSCs to TKI treatment. With an increasing number of CML patients receiving continuous TKI treatment, concerns regarding high financial burden, long-term side effects, and loss of compliance have generated interest in developing approaches to target residual LSCs to facilitate cessation of treatment and achieve cures.…”

“…16,17 Culture of CML cell lines with stromal cell-conditioned medium or with fibronectin is reported to result in resistance to IM. 18,19 In turn, IM treatment increases CXCR4-mediated migration of CML cell lines to BM mesenchymal stromal cells (MSCs) and results in increased cell cycle arrest and survival of quiescent cells. 20 Although these results with cell lines and murine models suggest that microenvironmental interactions could protect CML cells from TKI treatment, the role of the BM stromal microenvironment in protecting primary human CML LSCs from TKI treatment and the underlying molecular interactions are not well studied.…”

FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report

“…Increased Stat3 activity in leukemia cells contributes to therapy resistance. 2,3 Thus, it is no surprise that aberrant Stat3 activity is associated with more aggressive disease across a variety of malignancies. [4][5][6] In acute myeloid leukemia (AML), increased constitutive pY-Stat3, as detected by Western blot or electrophoretic mobility shift assay (EMSA), has been reported in 21% to 76% of adult patients 4,[7][8][9][10] and was associated with shorter time to relapse.…”