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RESEARCH PRODUCT

Rôle de Tif1gamma dans les différenciations granulo-monocytaire et macrophagique

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Chronic myelomonocytic leukemia (CMML) is a hematologic stem cell disease whose characteristics correspond to myelodysplastic/myeloproliferative syndroms (MDS/MPS). Hematopoietic conditional deletion of Tif1γ in mice leads to the development of a MDS/MPS, mimiking human CMML, when age is comprised between 6 to 10 months, defining Tif1γ as a tumour suppressor gene. Moreover, peritoneal macrophage population in these mice is decreased despite a monocytosis.The aims of my work were first to characterize in sick mice the myeloid population, and second to study macrophage differentiation. The myeloid population in Tif1γΔ/Δ mice is morphologically immature, with granulocytic and monocytic features. We demonstrated that phenotypic and molecular characteristics of this population are close to those observed in PMN-MDSC (polymorphonuclear myeloid-derived suppressor cells), suggesting that Tif1γ is a negative regulator gene of this myeloid subset. Furthermore, we showed that in vitro macrophage differentiation of myeloid progenitors upon CSF-1 treatment is altered. Decreased expression of CSF1-R (CSF-1 receptor) does not totally explain this alteration since dendritic cell differentiation is also abnormal, without alteration in GM-CSFR expression. Therefore, we hypothesize that S100A8 and S100A9 hyperexpression in Tif1γΔ/Δ mice is able to promote PMN-MDSC-like differentiation at the expense of macrophage and dendritic differentiations. In conclusion, Tif1γ is a major myelopoiesis regulator gene.