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ACUTE LYMPHOBLASTIC LEUKEMIA

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

Leukemia volume 37, pages 728–740 (2023)Cite this article

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.

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Fig. 1: Kdm6b is essential for maintenance of NOTCH1-mutant T-ALL cells.
Fig. 2: T-ALL cells undergo apoptosis in the absence of Kdm6b.
Fig. 3: Pro-tumorigenic function of Kdmb6 in T-ALL is demethylase-dependent.
Fig. 4: KDM6B is required to sustain disease in a subset of T-ALL patients.
Fig. 5: KDM6B restrains expression of pro-apoptotic genes in KDM6B-dependent T-ALLs.
Fig. 6: Genetic signature of KDM6B dependence in T-ALL.
Fig. 7: KDM6B protects T-ALL cells from strong NOTCH1 signaling-induced apoptosis.

Data availability

Primary RNA-sequencing data are available through NCBI Gene Expression Omnibus under GEO accession number GSE214576.

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Acknowledgements

We thank all members of the Challen laboratory for ongoing contributions and critical discussion. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and the Institute of Clinical and Translational Sciences (ICTS) at Washington for the use of the Tissue Procurement Core, which provided T-ALL patient samples. Support for the procurement of human samples was provided by P50CA171963. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant P30CA091842 and the ICTS is funded by the National Institutes of Health’s NCATS Clinical and Translational Science Award (CTSA) program grant UL1TR002345. We thank the Roswell Park Hematological Procurement Shared Resource for T-ALL specimens which is supported by the NCI Cancer Center Support Grant 5P30CA001656. We thank the Siteman Cancer Center Flow Cytometry core, which is supported by NIH Cancer Center Support Grant P30CA091842. We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for genomic analyses. The Center is partially supported by NCI Cancer Center Support Grant P30CA91842. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. This work was supported by the National Institutes of Health (HL147978, CA236819, and DK124883 to G.A.C), Gabrielle’s Angel Foundation (to G.A.C), Alex’s Lemonade Stand Foundation (to G.A.C) and the Children’s Discovery Institute (to G.A.C). C.R.Z. was supported by an American Society of Hematology post-doctoral scholar award and the Edward P. Evans Center for MDS Post-Doctoral Fellowship. Z.R. and K.G. were supported by the Intramural Research Program of NIDDK, NIH. E.S.W. is supported by the Jacquie Hirsch Leukemia Research Fund. G.A.C. is a scholar of the Leukemia and Lymphoma Society.

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Authors and Affiliations

  1. Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Nancy Issa, Hassan Bjeije, Elisabeth R. Wilson, Aishwarya Krishnan, Wangisa M. B. Dunuwille, Tyler M. Parsons, Christine R. Zhang, Wentao Han, Andrew L. Young, Amanda Cashen, David H. Spencer & Grant A. Challen

  2. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Zhizhong Ren & Kai Ge

  3. Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Eunice S. Wang

  4. Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada

    Andrew P. Weng

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Contributions

Conceptualization and study design—GAC. Experimentation and data acquisition—NI, HB, AK, WMBD, TMP, CRZ, WH, GAC Data analysis—NI, ERW, ALY, DHS, GAC. Resources, and reagents—ZR, KG, ESW, APW, AC. Funding acquisition—GAC. Project administration and supervision—GAC. Manuscript preparation—GAC.

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Correspondence to Grant A. Challen.

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G.A.C. has performed consulting and received research support from Incyte (unrelated to this work). The remaining authors have declared that no conflict of interest exists.

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Issa, N., Bjeije, H., Wilson, E.R. et al. KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress. Leukemia 37, 728–740 (2023). https://doi.org/10.1038/s41375-023-01853-9

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