title: 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.
authors.affiliation: Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Esposito
authors.affiliation: Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.
authors.forename: Tsz Kan
authors.initials: TK
authors.lastname: Fung
authors.affiliation: Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.
authors.forename: Jayant K
authors.initials: JK
authors.lastname: Rane
authors.affiliation: Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Cell Proliferation Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.affiliation: Cell Proliferation Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Jesus
authors.identifier: http://orcid.org/0000-0002-4303-6260
authors.initials: J
authors.lastname: Gil
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Anskar Y
authors.initials: AY
authors.lastname: Leung
authors.affiliation: University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Leukemia and Stem Cell Biology Group, Department of Haematological Medicine, Division of Cancer Studies, King's College London, London, UK.
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D009857:Oncogenes; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib