Acute myeloid leukemia (AML) is characterized by increased proliferation, evasion of apoptotic stimuli and block of differentiation. Mutations in FMS-like tyrosine kinase 3 (FTL3) receptor such as the internal tandem duplicate (FLT3-ITD) are found in about 25% of de novo AML cases. This mutation causes constitutive active downstream signaling and allows cells to replicate at a high proliferation rate. The question we like to address is how cells maintain genomic integrity in such conditions.
Poly (ADP-ribose) polymerase (PARP) is a family of proteins that are involved in various genome maintenance processes and play a major role in correcting single strand breaks (SSB). Perturbing highly proliferating cells by inhibiting PARP can induce genetic instability by increasing the number of double strand breaks (DSB). The recruitment of DSB repair pathway proteins to the site of damage can be quantified by an accumulation of γH2AX foci.
In this project we aim at shedding light in mechanisms involved in maintaining genomic stability, exploring pathways regulating DSB repair and exploit mechanisms that prevent induction of apoptosis in highly proliferating AML cells.