KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition.

Autor: Boila LD; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Ghosh S; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India., Bandyopadhyay SK; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India., Jin L; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Murison A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Zeng AGX; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada., Shaikh W; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India., Bhowmik S; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India., Muddineni SSNA; Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel., Biswas M; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA., Sinha S; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Chatterjee SS; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA., Mbong N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Gan OI; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Bose A; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India.; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India., Chakraborty S; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India., Arruda A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Kennedy JA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.; Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada.; Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada., Mitchell A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Lechman ER; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada., Banerjee D; Park Clinic, Gorky Terrace and Ramakrishna Mission Seva Pratisthan, Kolkata, 700017, West Bengal, India., Milyavsky M; Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel., Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.; Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada.; Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada., Dick JE; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. john.dick@uhnresearch.ca.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. john.dick@uhnresearch.ca., Sengupta A; Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India. amitava.sengupta@iicb.res.in.; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India. amitava.sengupta@iicb.res.in.; CSIR-IICB-Cancer Biology & Inflammatory Disorder Division, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India. amitava.sengupta@iicb.res.in.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2023 Apr; Vol. 37 (4), pp. 751-764. Date of Electronic Publication: 2023 Jan 31.
DOI: 10.1038/s41375-023-01833-z
Abstrakt: Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. Epigenetic deregulation contributes to AML pathogenesis. KDM6 proteins are histone-3-lysine-27-demethylases that play context-dependent roles in AML. We inform that KDM6-demethylase function critically regulates DNA-damage-repair-(DDR) gene expression in AML. Mechanistically, KDM6 expression is regulated by genotoxic stress, with deficiency of KDM6A-(UTX) and KDM6B-(JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations are implicated in chemoresistance, although a significant percentage of relapsed-AML has upregulated KDM6A. Olaparib treatment reduced engraftment of KDM6A-mutant-AML-patient-derived xenografts, highlighting synthetic lethality using Poly-(ADP-ribose)-polymerase-(PARP)-inhibition. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, BCL2A1 associates with venetoclax resistance, and KDM6A loss was accompanied with a downregulated BCL2A1. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support of a novel combination therapy for AML based on subtype-heterogeneity, and establishes KDM6A as a molecular regulator for determining therapeutic efficacy.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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