Abstract
Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene BCR-ABL1T315I differ from BCR-ABL1 native (BCR-ABL1) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin β3, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1T315I+ tumor burden and significantly prolonged survival of mice with BCR-ABL1T315I+ CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin β3/ILK-mediated signaling pathway in BCR-ABL1T315I+ cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.
Highlights
Resistance to cancer treatments may be due to cancer cellintrinsic mechanisms, such as alteration of the drug target, These authors contributed : Raquel S
Here we show that interactions of leukemic murine and human cells with the BMM via the fibronectin/integrin β3/ integrin-linked kinase (ILK)-mediated signaling pathway influence leukemia progression and clinical outcome in BCR-ABL1T315I+ imatinib-resistant chronic myeloid leukemia (CML) in vivo
Measuring the shortest threedimensional distance to the endosteum [17], we demonstrated that transplanted BCR-ABL1+ Lin− c-Kit+ Sca-1+ (LKS) cells, which harbor the leukemic stem cells (LSC) [19] in the retroviral transduction/transplantation model of CML [20], and, LKS CD150+ CD48− (SLAM) cells, were located significantly further away from the endosteum than control cells (P = 0.0029 and P = 0.0035, respectively, Figs. 1a, S1A and Supplementary Table 1)
Summary
Resistance to cancer treatments may be due to cancer cellintrinsic mechanisms, such as alteration of the drug target, These authors contributed : Raquel S. Global phosphoproteome analysis of BCR-ABL1T315I+ cells identified a unique signature of phosphosubstrates compared with cells positive for native BCR-ABL1 or other imatinibresistance conferring mutations leading to altered biological properties [15] Exactly how these leukemia cellintrinsic alterations might influence disease outcome, for instance via altered interactions with the BMM, has not been demonstrated. Here we show that interactions of leukemic murine and human cells with the BMM via the fibronectin/integrin β3/ integrin-linked kinase (ILK)-mediated signaling pathway influence leukemia progression and clinical outcome in BCR-ABL1T315I+ imatinib-resistant CML in vivo. Targeting these interactions may offer a beneficial, innovative, additive treatment strategy for patients with BCRABL1T315I+ CML, and possibly other leukemias
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