Early steps of haematopoietic transformation group
This group belongs to the UMR 1170 Normal and pathologic haematopoiesis
The overall aim of our group is to identify the acquired mutations in the early step of haematopoietic transformation, understand the network of cooperating events underlying transformation and develop experimental models to allow functional investigations and serve as preclinical models.
Most of the adult haematological malignancies arise from a pre-leukaemic phase that involves an infra-clinic expansion of abnormal, mutated haematopoietic stem/progenitor cells. It has been shown that genetic lesions in genes encoding for transcription factors (such as RUNX1, Spi1/PU.1), mRNA splicing (SF3B1, U2AF35), DNA methylation (Ten-Eleven-Translocation 2 (TET2), DNA (cytosine-5)-methyltransferase 3A (DNMT3A)), intermediate metabolism (Isocitrate Dehydrogenase 1 and 2 (IDH1/2)) or chromatin structure (SMC1A) are founding mutations in human malignancies. We are investigating the functional consequences of TET2, DNMT3A and IDH genetic lesions that frequently predate the development of myeloid or lymphoid malignancies and are involved in epigenetic gene regulation. We are studying the consequences of alteration in Spi1/PU activity, a transcriptional factor of the ETS family, which in addition to transcriptional regulation, plays a role in the control of epigenetic and RNA splicing regulation. In addition, we are analysing the roles of the GTPase RhoA and its regulators (GEFs & GAPs) during normal haematopoietic cell division and studying how mutations in RhoA may cooperate with epigenetic factors for lymphocyte transformation.