Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors

Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors,
which have been classically viewed as intractable targets using small molecule inhibitor
approaches. Here, we demonstrate that AML driven by repressive transcription factors
including AML1-ETO and PML-RARα are extremely sensitive to Poly (ADP-ribose)
Polymerase (PARP) inhibitor (PARPi), in part due to their suppressed expression of key
homologous recombination genes and thus compromised DNA damage response (DDR).
In contrast, leukemia driven by MLL fusions with dominant transactivation ability is
proficient in DDR and insensitive to PARP inhibition. Intriguing, depletion of an MLL
downstream target, Hoxa9 that activates expression of various HR genes, impairs DDR
and sensitizes MLL leukemia to PARPi. Conversely, Hoxa9 over-expression confers
PARPi resistance to AML1-ETO and PML-RARα transformed cells. Together, these
studies describe a potential utility of PARPi-induced synthetic lethality for leukemia
treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML.