Abstract B08: New Abelson interactor-1(Abi-1)-driven mechanism of acquired drug resistance

Abstract

Abstract In hematological malignancies, quiescent leukemic stem cells are responsible for persistence of minimal residual disease and relapse. We have recently identified a new signaling pathway that is significantly dysregulated in imatinib mesylate (IM) resistant leukemic cells (Chorzalska et all, Leukemia in press). A key player in this pathway is Abelson interactor-1 (Abi-1). Abi-1 was originally identified as Abl kinase associating protein that was later confirmed to be one of the Bcr-Abl interactors. Abi-1 was recently shown to interact directly with α4 integrin, which controls lodging of hematopoietic and leukemic stem cells (HSCs/LSCs) in the bone marrow microenvironment. We have recently obtained evidence that Abi-1 plays a role in signaling cross-talk between Bcr-Abl and α4 integrin. We have found that loss of Abi-1 leads to increased adhesion and quiescence, resulting in increased chemoresistance of leukemic CD34+ progenitor cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl positive CD34+ progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate (IM) resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug resistant phenotype of leukemic cells. Based on our findings, we hypothesize that chemoresistance arises as a consequence of dysregulation of a pathway involving α4 integrin and Abi-1, and is mediated through a previously unknown mechanism that is independent of oncogene activity. Citation Format: Anna Chorzalska, Ibrahem Salloum, Philip Marjon, Diana Treaba, Christoph Schorl, Morgan John, Christine R. Bryke, John Reagan, Eric Winer, Adam J. Olszewski, Patrycja M. Dubielecka. New Abelson interactor-1(Abi-1)-driven mechanism of acquired drug resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B08.