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

doi:10.1038/s41375-023-01833-z

. 2023 Apr;37(4):751-764.

doi: 10.1038/s41375-023-01833-z. Epub 2023 Jan 31.

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

Liberalis Debraj Boila^#^{1

2}, Subhadeep Ghosh^#^{1

3}, Subham K Bandyopadhyay^#^{1

3}, Liqing Jin⁴, Alex Murison⁴, Andy G X Zeng^{4

5}, Wasim Shaikh^{1

3}, Satyaki Bhowmik^{1

3}, Siva Sai Naga Anurag Muddineni⁶, Mayukh Biswas^{1

7}, Sayantani Sinha^{1

8}, Shankha Subhra Chatterjee^{1

9}, Nathan Mbong⁴, Olga I Gan⁴, Anwesha Bose^{1

3}, Sayan Chakraborty¹, Andrea Arruda⁴, James A Kennedy^{4

10

11}, Amanda Mitchell⁴, Eric R Lechman⁴, Debasis Banerjee¹², Michael Milyavsky⁶, Mark D Minden^{4

10

11

13}, John E Dick^{14

15}, Amitava Sengupta^{16

17

18}

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.
² Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
³ Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁶ Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.
⁷ Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA.
⁸ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
⁹ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
¹⁰ Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada.
¹¹ Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹² Park Clinic, Gorky Terrace and Ramakrishna Mission Seva Pratisthan, Kolkata, 700017, West Bengal, India.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. john.dick@uhnresearch.ca.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. john.dick@uhnresearch.ca.
¹⁶ 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.
¹⁷ 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.
¹⁸ CSIR-IICB-Cancer Biology & Inflammatory Disorder Division, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India. amitava.sengupta@iicb.res.in.

^# Contributed equally.

PMID: 36720973
DOI: 10.1038/s41375-023-01833-z

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

Liberalis Debraj Boila et al. Leukemia. 2023 Apr.

. 2023 Apr;37(4):751-764.

doi: 10.1038/s41375-023-01833-z. Epub 2023 Jan 31.

Authors

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.
² Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
³ Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁶ Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.
⁷ Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA.
⁸ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
⁹ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
¹⁰ Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, M5G 2C4, Canada.
¹¹ Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹² Park Clinic, Gorky Terrace and Ramakrishna Mission Seva Pratisthan, Kolkata, 700017, West Bengal, India.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. john.dick@uhnresearch.ca.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. john.dick@uhnresearch.ca.
¹⁶ 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.
¹⁷ 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.
¹⁸ CSIR-IICB-Cancer Biology & Inflammatory Disorder Division, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India. amitava.sengupta@iicb.res.in.

^# Contributed equally.

PMID: 36720973
DOI: 10.1038/s41375-023-01833-z

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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References

1. Tran N, Broun A, Ge K. Lysine demethylase KDM6A in differentiation, development, and cancer. Mol Cell Biol. 2020;40:e00341–20. - PubMed - PMC
1. Yu SH, Zhu KY, Chen J, Liu XZ, Xu PF, Zhang W, et al. JMJD3 facilitates C/EBPbeta-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun. 2018;9:3369. - PubMed - PMC
1. Ohguchi H, Harada T, Sagawa M, Kikuchi S, Tai YT, Richardson PG, et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia. 2017;31:2661–9. - PubMed - PMC
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1. Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94. - PubMed

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[1] Tran N, Broun A, Ge K. Lysine demethylase KDM6A in differentiation, development, and cancer. Mol Cell Biol. 2020;40:e00341–20. - PubMed - PMC

[2] Tran N, Broun A, Ge K. Lysine demethylase KDM6A in differentiation, development, and cancer. Mol Cell Biol. 2020;40:e00341–20. - PubMed - PMC

[3] Yu SH, Zhu KY, Chen J, Liu XZ, Xu PF, Zhang W, et al. JMJD3 facilitates C/EBPbeta-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun. 2018;9:3369. - PubMed - PMC

[4] Yu SH, Zhu KY, Chen J, Liu XZ, Xu PF, Zhang W, et al. JMJD3 facilitates C/EBPbeta-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun. 2018;9:3369. - PubMed - PMC

[5] Ohguchi H, Harada T, Sagawa M, Kikuchi S, Tai YT, Richardson PG, et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia. 2017;31:2661–9. - PubMed - PMC

[6] Ohguchi H, Harada T, Sagawa M, Kikuchi S, Tai YT, Richardson PG, et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia. 2017;31:2661–9. - PubMed - PMC

[7] Boila LD, Chatterjee SS, Banerjee D, Sengupta A. KDM6 and KDM4 histone lysine demethylases emerge as molecular therapeutic _targets in human acute myeloid leukemia. Exp Hematol. 2018;58:44–51.e7. - PubMed

[8] Boila LD, Chatterjee SS, Banerjee D, Sengupta A. KDM6 and KDM4 histone lysine demethylases emerge as molecular therapeutic _targets in human acute myeloid leukemia. Exp Hematol. 2018;58:44–51.e7. - PubMed

[9] Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94. - PubMed

[10] Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94. - PubMed

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

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

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