Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia

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-ABL1 T315I 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-ABL1 T315I+ tumor burden and significantly prolonged survival of mice with BCR-ABL1 T315I+ 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-ABL1 T315I+ 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.

The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms

“…In addition to intrinsic regulation, extrinsic regulation of the bone marrow microenvironment plays an important role in CML progression ( Kumar et al, 2020 ; Lefort and Maguer-Satta, 2020 ). Based on the findings of circulating lncRNAs, including H19 expression, we targeted the exosome compartment to investigate the potential regulatory role of LNC000093.…”

Recent advances in understanding chronic myeloid leukemia: where do we stand?

“…Knockdown or pharmacological inhibition of integrin-linked kinase (ILK), a protein of the adhesosome complex downstream of the integrins and upregulated in BCR-ABL1 T315I + cells, significantly delayed CML progression in vivo via increased levels of fibronectin, an extracellular matrix protein, in the BMM. Prolongation of survival in this CML model could also be achieved by the administration of fibronectin 73 . Expression of ILK was higher in LSCs of TKI non-responder patients, and inhibition of ILK sensitized these cells to TKIs.…”

Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

“…Ruxolitinb was tested in combination with nilotinib in CML patients with molecular disease (NCT01702064) or CML and Ph + acute lymphoblastic leukemia patients (NCT02253277). Furthermore, IL-6 was shown to activate JAK1-STAT3 signaling in CML LSC and co-inhibition of JAK1 and BCR-ABL1 reduced the colony forming ability of murine and human CML cells, even in quiescent cells [ 177 ]. Modulation of the Wnt/β-catenin signaling pathway by C82 or its prodrug PRI-274 and nilotinib led to the killing of imatinib-resistant BC-CML cells in vitro and prolonged survival in xenotransplantation models [ 178 ].…”