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

Abstract

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.

Roles of IDH1/2 and TET2 mutations in myeloid disorders

“…A combination approach may also be of benefit. In preclinical models of AML, PARP inhibitors are most effective in killing AML cells in which the HDR repair mechanism is also impaired [56]. Thus, it will be interesting to investigate the sensitivity of IDH1/2-and TET2-mutant AML to PARP inhibitors.…”

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

“…Previous data revealing the requirement for DOT1L activity in HOXA-overexpressing acute myeloid leukemia 21 suggest that pharmacological DOT1L inhibition might also have therapeutic benefit in T-ALL. In addition, recent evidence from in vitro and animal models suggests that combined inhibition of glycogen synthase kinase and poly(ADP-ribose) polymerase effectively suppresses growth of chemoresistant HOXA-overexpressing acute myeloid leukemia, 44 suggesting a similar potential avenue of investigation in HOXA Pos T-ALL.…”

“…Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0. 44). Multivariate analysis further revealed that HOXA positivity independently affected eventfree survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia.…”

Exploiting DNA damage repair defects for effective targeting of acute myeloid leukaemia by PARP inhibitors

“…Leukemic cells driven by the oncofusion genes, AML1-ETO and PML-RARα, are sensitive to PARP inhibition whereas cells harbouring MLL-AF9 translocation are resistant [8]. …”

“…More importantly, we showed for the first time that HoxA9 can activate a potential DNA repair back-up pathway. PARPi in combination with pharmacological inhibitors of HOXA9 may represent a novel avenue for tailored therapeutic targeting of the aggressive MLL leukaemia [8].…”