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ACUTE MYELOID LEUKEMIA

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

Leukemia volume 37, pages 751–764 (2023)Cite this article

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Abstract

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.

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Fig. 1: KDM6 demethylases associate with DNA repair gene expression in AML.
Fig. 2: Loss of KDM6 in AML cells impairs DDR gene expression and double-stranded break (DSB) repair.
Fig. 3: KDM6A regulates chromatin architecture at DDR loci.
Fig. 4: KDM6A deficiency sensitizes AML to PARP inhibition.
Fig. 5: KDM6A associates with BCL2 and BCL2A1 expression.
Fig. 6: Attenuation of KDM6 increases AML susceptibility to BCL2 blockade.
Fig. 7: KDM6A-domain mutant primary AML cells are even more sensitive to combination of PARP and BCL2 blockade.

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Data availability

RNA-seq and ATAC-seq datasets are deposited in the Gene Expression Omnibus (GEO) with an accession number GSE223610.

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Acknowledgements

We thank Drs. Kristian Helin (Addgene# 24168), Kai Ge (Addgene# 40619), Didier Trono (Addgene# 12260, 12259), Tomasz Skorski, and Steven Chan for sharing plasmid constructs and cells. We also thank Alexander Avgoustis for helping with AML specimens through Leukemia Tissue Bank at Princess Margaret Cancer Centre/University Health Network. We acknowledge Nicholas Khuu, Julissa Tsao (Princess Margaret Genomics Centre, Toronto), and Drs. Arindam Maitra, Disha Banerjee, Subrata Patra (National Genomics Core/Co-TERI, National Institute of Biomedical Genomics, Kalyani, India) for next-generation sequencing services, Princess Margaret (UHN) Animal Resources Centre, Flow Cytometry Core, CSIR-IICB Flow Cytometry, Central Instrumentation, Radiation Facility, Bidhan Chandra Krishi Viswa Vidyalaya Radiation Facility and Dr. Arunima Maiti, Tata Translational Cancer Research Center (TTCRC) for Flow Cytometry sorting facility and experimental help. We thank Dr. Nabanita Dasgupta, NRS Medical College & Hospital for providing umbilical cord blood samples. We are grateful to Dr. Craig Jordan (U Colorado) for sharing transcriptome datasets of venetoclax-resistant Mono-AML, and we appreciate his comments during the preparation of this manuscript. We also thank Drs. Stephanie Xie, Helena Boutzen, Jean Wang, and other members of the Sengupta and Dick laboratories for comments and helpful discussions, and Sally Desilva, Monica Doedens for administrative assistance. This study is supported by funding from Council for Scientific & Industrial Research (CSIR) (HCP-0008, HCP-23 and P07/MLP-AS/578), Department of Biotechnology (DBT) (BT/RLF/RE-ENTRY/06/2010), Ramalingaswami Fellowship (to AS), DBT (BT/PR13023/MED/31/311/2015) (to AS), and Department of Science & Technology (DST) (SB/SO/HS-053/2013), Govt. of India (to AS). AS was a Visiting Scientist in JED laboratory at Princess Margaret Cancer Centre, Toronto, supported by Indian Council of Medical Research (ICMR)-DHR (Short-Term) International Fellowship (INDO/FRC/452/S-11/2019-20-lHD). JED acknowledges funding from the: Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research (OICR) with funding from the Province of Ontario, Canadian Institutes for Health Research (Foundation: 154293, Operating Grant 130412, Operating Grant 89932, and Canada-Japan CEEHRC Teams in Epigenetics of Stem Cells 127882); International Development Research Centre, Canadian Cancer Society (703212); Terry Fox Research Institute Program Project Grant; University of Toronto’s Medicine by Design initiative, which receives funding from the Canada First Research Excellence Fund; and a Canada Research Chair. MM acknowledges support from Israel Science Foundation (ISF 1512/14), Varda and Boaz Dotan Research Center in Hemato-Oncology, and Israel Cancer Research Fund (RCDA 14-171). LDB was a recipient of CSIR-Shyama Prasad Mukherjee Fellowship. SG, WS, SB, AB acknowledge research fellowships from CSIR and SKB thanks DBT for financial support. SS, SSC, and MB, SC received funding from CSIR and UGC, respectively.

Author information

Author notes

  1. Liberalis Debraj Boila

    Present address: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

  2. Mayukh Biswas

    Present address: Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA

  3. Sayantani Sinha

    Present address: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

  4. Shankha Subhra Chatterjee

    Present address: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA

  5. These authors contributed equally: Liberalis Debraj Boila, Subhadeep Ghosh, Subham K. Bandyopadhyay.

Authors and Affiliations

  1. Stem Cell & Leukemia Lab, CSIR-Indian Institute of Chemical Biology, IICB-Translational Research Unit of Excellence, Salt Lake, Kolkata, 700091, West Bengal, India

    Liberalis Debraj Boila, Subhadeep Ghosh, Subham K. Bandyopadhyay, Wasim Shaikh, Satyaki Bhowmik, Mayukh Biswas, Sayantani Sinha, Shankha Subhra Chatterjee, Anwesha Bose, Sayan Chakraborty & Amitava Sengupta

  2. Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India

    Subhadeep Ghosh, Subham K. Bandyopadhyay, Wasim Shaikh, Satyaki Bhowmik, Anwesha Bose & Amitava Sengupta

  3. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada

    Liqing Jin, Alex Murison, Andy G. X. Zeng, Nathan Mbong, Olga I. Gan, Andrea Arruda, James A. Kennedy, Amanda Mitchell, Eric R. Lechman, Mark D. Minden & John E. Dick

  4. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Andy G. X. Zeng & John E. Dick

  5. Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel

    Siva Sai Naga Anurag Muddineni & Michael Milyavsky

  6. Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada

    James A. Kennedy & Mark D. Minden

  7. Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada

    James A. Kennedy & Mark D. Minden

  8. Park Clinic, Gorky Terrace and Ramakrishna Mission Seva Pratisthan, Kolkata, 700017, West Bengal, India

    Debasis Banerjee

  9. Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada

    Mark D. Minden

  10. CSIR-IICB-Cancer Biology & Inflammatory Disorder Division, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India

    Amitava Sengupta

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  1. Liberalis Debraj Boila
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Conception, study design, and interpretation: AS. Experimental design, data acquisition, analysis, and interpretation: LDB, SG, SKB. Immunoblot analysis: WS, SSC. Biochemical studies: SB, MB, SS, AB, SC. Xenotransplantation and pharmacological studies: LJ, NM, OIG, AS. Drug sensitivity and cell survival assays: SG, SKB. Drug combination index analysis: WS, SB. ATAC-seq, RNA-seq, and computational analysis: AMu. RNAi screening: SSNAM, MM. Bioinformatics analysis: LDB, SG, AGXZ, MB. AML tissue banking and characterization: AA, JAK, A. Mi., ERL, DB, MDM. Manuscript writing: LDB, AS. Research direction, resources, fund acquisition, manuscript editing, and overall supervision: JED, AS. All authors have contributed and agreed with the final version of the manuscript.

Corresponding authors

Correspondence to John E. Dick or Amitava Sengupta.

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Competing interests

JED Celgene: Research Funding; Trillium Therapeutics/Pfizer: patents for Sirp-a targeting; Graphite Bio: SAB. MDM Astellas: Consultancy. No potential conflicts of interest are disclosed by the other authors.

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Boila, L.D., Ghosh, S., Bandyopadhyay, S.K. et al. KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition. Leukemia 37, 751–764 (2023). https://doi.org/10.1038/s41375-023-01833-z

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