Research Summary

Study the role of cell adhesion mediated drug resistance in Acute Promyelocytic Leukaemia treated with Arsenic trioxide and evaluate the potential role of drugs that can inhibit it.

Acute promyelocytic leukaemia (APL) is a sub type of acute myeloid leukaemia (AML) characterized by a reciprocal translocation, t (15; 17). Arsenic trioxide (ATO) in a dose dependent manner can induce differentiation or apoptosis of promyelocytic blasts in APL. Therapy with ATO is cost effective and as reported by us is effective in inducing durable remissions, even as a single agent, in newly diagnosed cases of APL. However, relapses do occur in 10–20% of newly diagnosed cases and in up to 60% of relapsed patients treated with this agent alone. Cell adhesion mediated resistance (CAMDR) of malignant cells by modulating anti-apoptotic gene expression and favouring quiescence can result in drug resistance. Preliminary data from our laboratory has demonstrated that this may be an important mechanism by which malignant promyelocytes survive the apoptotic action of ATO and that this effect appears to be mediated predominantly via the NFkB pathway. We have also demonstrated that use of agents that inhibit either the malignant promyelocyte and stromal interaction or the NFkB pathway can overcome such resistance. We are in the process of evaluating in detail the mechanisms of CAMDR to ATO in APL and potentially identify additional targets that could be targeted for therapeutic interventions.

 

Figure Legend: Prominent pathways altered in APL by gene expression array comparing newly diagnosed and relapsed patients. Potential mechanism contributing to disease recurrence