PARP Inhibitors Suppress AML1–ETO- and PML–RARα-Positive Leukemia

Acute myeloid leukemia (AML) is characterized by transcription factor fusion proteins, including runt-related transcription factor 1 (RUNX1)–RUNX1T1 (also known as AML1–ETO), promyelocytic leukemia (PML)–retinoic acid receptor α (RARα), and lysine (K)-specific methyltransferase 2A [KMT2A, also known as mixed lineage leukemia (MLL)] fusions, which function as oncogenic drivers. However, there are no targeted therapies against these fusions, and AML treatment is generally limited to toxic chemotherapy. In an effort to identify synthetic lethal therapeutic approaches for AML, Esposito and colleagues treated primary mouse hematopoietic cells transformed by leukemia-associated transcription factors with PARP inhibitors. PARP inhibition or knockdown reduced colony formation in cells expressing AML1–ETO or PML–RARα, but not MLL–AF9 or E2A–PBX. Similar results were observed in patient-derived leukemia cell lines and in mouse xenografts. Additionally, PARP inhibition induced differentiation into monocytic and granulocytic lineages, G1 cell-cycle arrest, and senescence in AML1–ETO- and PML–RARα-transformed cells, but not MLL–AF9- or E2A–PBX-transformed cells. AML cells exhibited DNA damage or replication stress marked by high levels of γH2AX DNA damage foci, which were further induced by PARP inhibition. However, in contrast to E2A–PBX- and MLL–AF9-transformed cells, AML1–ETO and PML–RARα cells did not efficiently recruit RAD51, indicating a defect in homologous recombination (HR)–mediated double-strand break repair. MLL–AF9-transformed cells induced expression of HOXA9, which promoted resistance to PARP inhibition; HOXA9 deletion or suppression of HOXA9 function via inhibition of glycogen synthase kinase 3 sensitized MLL leukemic cells to PARP inhibition and impaired MLL leukemia growth. Conversely, HOXA9 overexpression in AML1–ETO- and PML–RARα-transformed cells increased RAD51 recruitment to DNA damage foci, enhanced HR efficiency, and reduced sensitivity to PARP inhibition. Together, these data indicate that PARP inhibitors effectively target AML1–ETO- and PML–RARα-positive leukemia, and suggest that HOXA9 inhibition may sensitize AML cells to PARP inhibitors.

Esposito MT, Zhao L, Fung TK, Rane JK, Wilson A, Martin N, et al. Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med 2015;21:1481–90.

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