RESUMO
Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Monócitos/metabolismo , Animais , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Recém-Nascido , Fatores Inibidores da Migração de Macrófagos/genética , CamundongosRESUMO
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that typically associates with mutations in epigenetic, splicing, and signaling genes. Genetically modified mouse models only partially recapitulate the disease phenotype, whereas xenotransplantation of CMML cells in immunocompromised mice has been rarely successful so far. Here, CMML CD34+ cells sorted from patient bone marrow (BM) or peripheral blood (PB) were injected intravenously into NSG (NOD/LtSz-scid IL2rγnull) mice and NSG mice engineered to express human granulo-monocyte colony-stimulating factor, stem cell factor, and interleukin-3 (NSGS mice). Fifteen out of 16 patient samples (94%) successfully engrafted into NSG or NSGS or both mouse strains. The expansion of human cells, predominant in the BM, was also observed in the spleen and the PB and was greatly enhanced in mice producing the 3 human cytokines. Gene mutations identified in engrafted cells were mostly similar to those identified in patient cells before injection. Successful secondary engraftment was obtained in NSGS mice in 3 out of 10 attempts. Thus, primary CMML leukemic cells expand much better in NSGS compared with NSG mice with limited efficacy of secondary transplant.
