Abstract 2538: Investigating the role of the oncogenic miR-17-92 cluster as involved in TKI-resistance enhancing the survival of MYB-dependent Ph+ acute lymphoblastic leukemia cells

Abstract

Abstract BackgroundThe Philadelphia (Ph) chromosome generates aberrant BCR-ABL constitutively active proteins, and represents the most frequent cytogenetic abnormality in acute lymphoblastic leukemia (ALL). BCR-ABL is an ideal target for Ph+ leukemia treatment, thus tyrosine kinase inhibitors (TKIs) were developed as therapeutic drugs. Although such drugs have markedly improved the Ph+ ALL outcome, many patients develop resistance to TKIs treatment, frequently associated with point mutations or amplification of the BCR-ABL gene, but also with the activation of BCR-ABL-independent pathways. MicroRNAs (miRNAs) play a critical role in pharmacogenomics regulating the expression of genes essential for drug activity. Aberrant miRNAs expression may be involved in BCR-ABL-dependent/independent TKI-resistance mechanisms, among them members of miR-17-92 cluster. We previously showed that modulation of the oncogenic miR-17-92 cluster, a direct target of the transcription factor MYB, rescued the impaired proliferation and enhanced apoptosis of MYB-silenced Ph+ ALL cells, indicating that de-regulated miRNAs are involved in the MYB “addiction” of Ph+ ALL. Members of miR-17-92 cluster were reported to be involved in TKI-resistance, but MYB expression is not affected by TKIs treatment in Ph+ cells, suggesting that MYB-dependent pathways could have a role in BCR-ABL-independent mechanisms of drug resistance. AimTo evaluate the relationship between the miR-17-92 cluster, its target genes and resistance to tyrosine kinase inhibitors. ResultsWe assessed the cell survival in miR-17-92-overexpressing compared to empty vector (EV) Ph+ ALL cells, after TKIs treatment. The results showed that miR-17-92 cluster contributes in promoting the survival of Ph+ ALL TKI-treated cells. We evaluated the cell death through the apoptotic markers, observing that overexpressing miR-17-92 cells showed less apoptosis than EV cells, after TKI-treatment. We analyzed the MYB protein and miR-17-92 expression in miR-overexpressed compared to EV cells. We found that both MYB and miR-17-92 levels are not modulated by TKI treatment indicating a possible activation of alternative pathways under their control operating despite effective TKI inhibition of BCR-ABL1. Thus, our data underscore the importance of investigating the role of miR-17-92 cluster in TKI-resistant Ph+ leukemia cells. This might help to reveal a strategy for new therapeutic approaches in drug resistance. ConclusionsThese data suggest that the miR-17-92 cluster might exert anti-apoptotic and pro-proliferative effects in Ph+ acute lymphoblastic leukemia cells after TKIs treatment and investigating its biological role may lead to future breakthroughs in TKI-resistant Ph+ leukemia. Citation Format: Manuela Spagnuolo, Giulia Regazzo, Andrea Sacconi, Ana B. Díaz Méndez, Bruno Calabretta, Maria G. Rizzo. Investigating the role of the oncogenic miR-17-92 cluster as involved in TKI-resistance enhancing the survival of MYB-dependent Ph+ acute lymphoblastic leukemia cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2538.