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

Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE

Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-

DNA-Binding Proteins*/deficiency ; DNA-Binding Proteins*/genetics ; DNA-Binding Proteins*/metabolism ; Dioxygenases*/deficiency ; Dioxygenases*/genetics ; Dioxygenases*/metabolism ; Jumonji Domain-Containing Histone Demethylases*/biosynthesis ; Jumonji Domain-Containing Histone Demethylases*/genetics ; Leukemia, Myelomonocytic, Chronic*/genetics ; Leukemia, Myelomonocytic, Chronic*/metabolism ; Leukemia, Myelomonocytic, Juvenile*/genetics ; Leukemia, Myelomonocytic, Juvenile*/metabolism; Animals ; Gene Expression Profiling ; Genome ; Humans ; Loss of Function Mutation ; Mice ; Mutation ; Proto-Oncogene Proteins/genetics

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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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0 (DNA-Binding Proteins)
0 (Proto-Oncogene Proteins)
EC 1.13.11.- (Dioxygenases)
EC 1.13.11.- (TET2 protein, human)
EC 1.13.11.- (Tet2 protein, mouse)
EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
EC 1.14.11.- (KDM6B protein, human)
EC 1.5.- (Kdm6b protein, mouse)

Date Created: 20220613 Date Completed: 20220803 Latest Revision: 20220808

20240105

10.1038/s41375-022-01605-1

35697791