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1.
Leuk Lymphoma ; 63(13): 3154-3164, 2022 12.
Article in English | MEDLINE | ID: mdl-36059252

ABSTRACT

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.


Subject(s)
Leukemia, Myelomonocytic, Chronic , Myelodysplastic Syndromes , Animals , Mice , Azacitidine/pharmacology , Azacitidine/therapeutic use , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/genetics , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Imidazoles/therapeutic use
2.
Leukemia ; 36(8): 2097-2107, 2022 08.
Article in English | MEDLINE | ID: mdl-35697791

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.


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