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 (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RARα fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression 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.

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Figure 1: PARPi targets AML1-ETO– and PML-RARα–transformed leukemic cells in vitro and in vivo.
Figure 2: PARPis induce differentiation, senescence, and apoptosis of AML1-ETO– and PML-RARα–transformed leukemic cells.
Figure 3: AML1-ETO– and PML-RARα–transformed cells show a defect in the HR pathway and accumulate DNA damage in response to PARPi treatment.
Figure 4: HOXA9 modulates sensitivity to PARPi.
Figure 5: HOXA9 modulates PARPi sensitivity.
Figure 6: Combined PARPi and GSK3i treatment impairs in vivo survival of MLL leukemia cells.

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Acknowledgements

We thank G. Mufti, S. Shall, T. Ng, and D. Weekes for insightful discussion; A. Zelent (Miller School of Medicine, University of Miami), M. Greaves (The Institute of Cancer Research, London ) and O. Heidenreich (Northern Institute for Cancer Research, Newcastle University) for providing NB4-LR2, THP1 and Kasumi cell lines, respectively; I. Ahel (Sir William Dunn School of Pathology, University of Oxford), I. Gibbs-Seymour (Sir William Dunn School of Pathology, University of Oxford), and D. Livingston (Dana-Farber Cancer Institute, Harvard University) for tagged ALPF and PARP1 constructs; E. Soutoglou (Institut de Genetique de Biologie Moleculaire et Celluraire) and M. Jasin (Memorial Sloan Kettering Cancer Center) for DR-GFP HR reporter systems; H. Lee (School of Biological Sciences, Seoul National University) and M. Tarsounas (Oxford University for Radiation Oncology) for BRCA2-specific antibody; J. Hess (Department of Pathology, University of Michigan School of Medicine) for the MSCV-HA-Hoxa9-IRES-GFP construct; C. Lourenco and W. Vetharoy for technical assistance with mice experiments and FACS analysis; S. Tung, A. Innes and P. Lau for technical assistance with gene expression profiling; T. Gaymes for support with DNA damage repair experiments; and P. Tse for graphical illustration. This work was supported by program grants from Bloodwise and Cancer Research UK (to C.W.E.S.).

Author information

M.T.E., L.Z. T.K.F. and J.K.R. performed experiments and analyzed the data. A.W. provided technical support for the in vivo experiments. N.M. and J.G. performed mass spectrometry and data analysis. A.Y.L. and A.A. provide essential reagents and data interpretation. M.T.E and C.W.E.S. wrote the manuscript. C.W.E.S. conceptualized, designed and supervised the study.

Correspondence to Chi Wai Eric So.

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Competing interests

A.A. has a consulting or advisory role at Genentech, Sun Pharma, GlaxoSmithKline, and Novartis; he also is a co-inventor on patents (US patent nos. US7449464, US7981889, US7692006, US8247416) related to the use of PARP inhibitors held by AstraZeneca. As a consequence, A.A. has and may in the future benefit financially from the Institute of Cancer Research's ‘rewards to inventors’ scheme.

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Esposito, M., Zhao, L., Fung, T. et al. Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med 21, 1481–1490 (2015). https://doi.org/10.1038/nm.3993

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