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MYELODYSPLASTIC SYNDROME

Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia

Leukemia volume 36, pages 2097–2107 (2022)Cite this article

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Abstract

Loss-of-function TET2 mutations are recurrent somatic lesions in chronic myelomonocytic leukemia (CMML). KDM6B encodes a histone demethylase involved in innate immune regulation that is overexpressed in CMML. We conducted genomic and transcriptomic analyses in treatment naïve CMML patients and observed that the patients carrying both TET2 mutations and KDM6B overexpression constituted 18% of the cohort and 42% of patients with TET2 mutations. We therefore hypothesized that KDM6B overexpression cooperated with TET2 deficiency in CMML pathogenesis. We developed a double-lesion mouse model with both aberrations, and discovered that the mice exhibited a more prominent CMML-like phenotype than mice with either Tet2 deficiency or KDM6B overexpression alone. The phenotype includes monocytosis, anemia, splenomegaly, and increased frequencies and repopulating activity of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Significant transcriptional alterations were identified in double-lesion mice, which were associated with activation of proinflammatory signals and repression of signals maintaining genome stability. Finally, KDM6B inhibitor reduced BM repopulating activity of double-lesion mice and tumor burden in mice transplanted with BM-HSPCs from CMML patients with TET2 mutations. These data indicate that TET2 deficiency and KDM6B overexpression cooperate in CMML pathogenesis of and that KDM6B could serve as a potential therapeutic target in this disease.

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Fig. 1: Co-occurrence of TET2 mutations and KDM6B overexpression in human CMML.
Fig. 2: Tet2 deficient mice with KDM6B overexpression display enhanced CMML-like phenotypes.
Fig. 3: Tet2 deficiency and KDM6B overexpression affects BM HSPC numbers and function.
Fig. 4: Transcriptional alterations in of BM HSPCs in mice with concurrent Tet2 deficiency and KDM6B overexpression.
Fig. 5: Targeting KDM6B alters BM repopulating capability of double-lesion BM cells.
Fig. 6: Targeting KDM6B decreases human cell chimerism in PDX models of CMML.

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Acknowledgements

We also acknowledge Cancer Prevention & Research Institute of Texas award RP101320 that supported our initial study about KDM6B in MDS and CMML.

Funding

This work was supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672, the generous philanthropic donations to the University of Texas MD Anderson MDS/AML Moon Shot, the Leukemia Research Foundation, and the Leukemia SPORE Development Award.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yue Wei, Hong Zheng, Naran Bao, Pamela Pennington Lockyer, Hui Yang, Guillermo Montalban-Bravo, Irene Ganan-Gomez, Kelly A. Soltysiak, Simona Colla & Guillermo Garcia-Manero

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rashmi Kanagal-Shamanna

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Caleb A. Class, Faezeh Darbaniyan & Kim-Anh Do

  4. Department of Epigenetic & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yue Lu & Kevin Lin

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Contributions

YW: Concept and design; collection and assembly of data; data analysis and interpretation; manuscript writing; and final approval of manuscript. RK-S, HZ, NB, PPL, CC, FD, YL, KL, HY, GM-B, IG-G, K-AD, SC: Collection and assembly of data; data analysis and interpretation; manuscript writing; and final approval of manuscript. KAS: Administrative support; data analysis and interpretation; manuscript writing; and final approval of manuscript. GG-M: Conception and design; administrative support; provision of study materials or patients; collection and assembly of data; manuscript writing; and final approval of manuscript.

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Correspondence to Yue Wei or Guillermo Garcia-Manero.

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Wei, Y., Kanagal-Shamanna, R., Zheng, H. et al. Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia. Leukemia 36, 2097–2107 (2022). https://doi.org/10.1038/s41375-022-01605-1

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