BRCAness in FLT3-ITD AML confers vulnerability to PARP inhibition

Abstract BReast CAncer ( BRCA1 and BRCA2 ) is a tumor suppressor gene that plays an important role in the repair of double strand DNA break (DSB) via error-free homologous recombination (HR). BRCA1 and BRCA2 mutations induce vulnerability to PARP inhibition, known as synthetic lethality, in breast and ovarian cancers but is rare in acute myeloid leukemia (AML). We demonstrated that AML carrying internal tandem duplication (ITD) of FMS-like Tyrosine Kinase 3 (FLT3) was vulnerable to DNA repair inhibition by poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), resulting in DNA damage, DSB and sensitization to genotoxic chemotherapy. FLT3 -ITD AML showed BRCA2 down-regulation at transcript and protein levels and decrease in homologous recombination in both primary samples and AML cell lines, reminiscent of “BRCAness”. BRCA2 expression was regulated by its transcription repressor SNAI1 . PARPi induced increase in interferon signaling, decrease in double-strand break repair, activation of cGAS-STING signaling and macrophage functions. Furthermore, PARPi upregulated AXL expression. Both AXL inhibition and knock-out accentuated the anti-leukemia effects of PARPi. Taken together, we identified a hitherto undescribed FLT3-ITD/SNAI1/BRCA2 axis in AML, a non-cell autonomous effect of PARPi via cGAS-STING activation and AXL as a therapeutic target, providing new therapeutic insights to FLT3 -ITD AML. Significance BRCA2 downregulation and decreased homologous recombination provide novel therapeutic option in FLT3-ITD AML Combined PARP and AXL inhibitors induced synergistic anti-leukemic effects in FLT3-ITD AML.