Cooperation between KDM6B overexpression and TET2 deficiency in the pathogenesis of chronic myelomonocytic leukemia.
Animals
DNA-Binding Proteins
/ deficiency
Dioxygenases
/ deficiency
Gene Expression Profiling
Genome
Humans
Jumonji Domain-Containing Histone Demethylases
/ biosynthesis
Leukemia, Myelomonocytic, Chronic
/ genetics
Leukemia, Myelomonocytic, Juvenile
/ genetics
Loss of Function Mutation
Mice
Mutation
Proto-Oncogene Proteins
/ genetics
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
22
12
2021
accepted:
12
05
2022
revised:
11
05
2022
pubmed:
14
6
2022
medline:
4
8
2022
entrez:
13
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35697791
doi: 10.1038/s41375-022-01605-1
pii: 10.1038/s41375-022-01605-1
doi:
Substances chimiques
DNA-Binding Proteins
0
Proto-Oncogene Proteins
0
Dioxygenases
EC 1.13.11.-
TET2 protein, human
EC 1.13.11.-
Tet2 protein, mouse
EC 1.13.11.-
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM6B protein, human
EC 1.14.11.-
Kdm6b protein, mouse
EC 1.5.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2097-2107Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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