Abstract LB-350: Abelson interactor-1 (Abi1) expression levels as a prognostic and drug resistance marker in Bcr-Abl positive leukemias.

Abstract

Abstract In hematological malignancies, quiescent leukemic stem cells are responsible for persistence of minimal residual disease and relapse. Emerging evidence points to the involvement of the bone marrow microenvironment in survival and systemic retention of leukemic stem/progenitor cells. Integrins, particularly α4β1, which controls hematopoietic stem cell trafficking, were shown to be required for leukemic stem cells lodging to the bone marrow niche, and were shown to be crucial for the persistence of minimal residual disease. The molecular mechanism governing these processes is not known. We have just recently obtained evidence that newly identified α4 integrin-Abelson interactor 1 (Abi1) signaling cross-talk is involved in acquired drug resistance in Bcr-Abl positive leukemic cells. Our data also indicated that Abi1 and α4 integrin may be useful as prognostic markers of treatment outcome in patients with relapsing Bcr-Abl positive leukemia. Comparison of mRNA levels of Abi1 and α4 integrin in Bcr-Abl positive CD34+ progenitor cells isolated from blood or bone marrow of CML (chronic myelogenous leukemia) patients at diagnosis and at relapse revealed significant decrease in mRNA levels of Abi1 and increase in mRNA levels of α4 integrin in relapsing CD34+ progenitor cells. Subsequent analyses performed on various imatinib mesylate (IM) resistant cell lines including K562, LAMA-84 or Bcr-Abl supplemented Ba/F3 cells, confirmed abnormal expression of Abi1 and α4 integrin, both mRNA and protein levels. IM resistant cells also exhibited acquired anchorage-dependent phenotype and enhanced adhesive properties. Further detailed analyses of α4 integrin-dependent pathways revealed significant de-regulation of integrin α4 downstream signaling being due to the abnormal expression of Abi1, what resulted in elevated levels of phospho-Akt (Ser472), phospho-Erk (Thr202/Tyr204) and abnormal JNK/SAPK and p38MAPK phosphorylation signals. In summary, our results not only indicate that Abi1 and α4 integrin may serve as potentially useful prognostic markers of treatment outcome in patients with relapsing Bcr-Abl positive leukemia, but also suggest that newly identified α4 integrin-Abi1-Bcr-Abl cross-talk may play a significant role in the interactions between leukemic progenitor cells and the bone marrow microenvironment, and alterations in this signaling mediate acquisition of the drug resistant phenotype of leukemic cells and contribute to the mechanisms of acquired drug resistance. Citation Format: Anna D. Chorzalska, Ibrahem Salloum, Hammad Shafqat, Saad Khan, Philip Marjon, Vincent Falanga, Ting Zhao, John Reagan, Eric Winer, Samer Al-Homsi, Nicola Kouttab, Patrycja M. Dubielecka. Abelson interactor-1 (Abi1) expression levels as a prognostic and drug resistance marker in Bcr-Abl positive leukemias. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-350. doi:10.1158/1538-7445.AM2013-LB-350