Institut de recherche en immunologie et en cancérologie (IRIC)
T 514 343-6970
Our team is composed of postdoctoral fellows, graduate students and technical personnel, whose research theme consists in defining how hematopoietic stem cells integrate various signals to self-renew or to launch a differentiation program and how this code is disrupted in leukemia. Our observations indicate that the SCL transcription factor, a member of the basic helix-loop-helix family of proteins, is important for the long-term maintenance of hematopoietic stem cells. In addition, SCL interacts with LMO1 or LMO2 and inhibits differentiation in the B and T lymphoid lineages. Interestingly, the genes coding for these three proteins are often activated in childhood T cell leukemias. Our work aims at understanding the mechanisms of leukemogenesis induced by these oncogenes, by a multidisciplinary approach that combines molecular genetics, functional genomics and proteomics with the analysis of transgenic mice or of knock-out mice. We observe that SCL blocks thymocyte differentiation and induces leukemia in transgenic mice by disrupting a combinatorial code between the E2A, HEB transcription factors and signalling by the pre-TCR. In addition, our research aims at understanding how SCL and LMO2 influence normal hematopoietic cell fate. Our work reveals that the differentiation of erythroid progenitors is determined by an epigenetic switch which controls the transition between a proliferative state and a commitment towards teminal differentiation. This epigenetic switch is controlled by the stoichiometry between the SCL transcription factor and the ETO2 co-repressor. Thus, the transcriptional activity of the SCL complex is maintained in check by the ETO2 co-repressor in hematopoietic stem cells and progenitors. On reception of a differentiation signal, the stochiometry tips in favor of SCL, thus overriding the repressive effect of ETO2 and allowing for activation of a gene expression program controlled by the SCL complex, i.e. erythroid genes and antiproliferative genes (p21Cdkn1a, Gfi-1b). Thus this complex coordinates growth cessation with erythroid differentiation, indicating that the SCL complex acts as a master regulator of this lineage. Our current work aims at determining the protein networks that interact with SCL and its partners by proteomic analysis. Finally, our recent work indicates that myeloid differentiation is controlled by a distinct transcriptional complex which implicates the PU.1, c-Jun and C/EBPb transcription factors.
- Mathieu Tremblay, Cedric S Tremblay, Sabine Herblot, Peter D Aplan, Josée Hébert, Claude Perreault and Trang Hoang. Modeling acute T-cell lymphoblastic leukemia induced by the SCL and LMO1 oncogenes. Genes Dev. 2010 24: 1093-1105.
- Julie Lacombe, Sabine Herblot, Rojas-Sutterlin Shanti, André Haman, Stephane Barakat, Norman N Iscove, Guy Sauvageau, and Trang Hoang. Scl sustains the quiescence and long term competence of hematopoietic stem cells. Blood, 115 (4): 792-803, 28 January 2010. (Inside Blood analysis by Brian P. Sorrentino. Scl and stem cell quiescence Blood 2010 115: 751-752)
- Hoang Trang. Of mice and men: how LMO2 transgresses the limits in T-cell acute lymphoblastic leukemia. Perspectives, Science Translational Medicine. Volume 2, 21ps10, March 2010. Invited review article
- Benoit Grondin, Martin Lefrancois, Mathieu Tremblay, Marianne Saint-Denis, André Haman, Kazuo Waga, André Bédard, Daniel G Tenen, Trang Hoang, c-Jun as a context-specific coactivator. Mol Cell Biol.27(8): 2919-2933, 2007.
- Nicolas Goardon, Julie Alexandra Lambert, Patrick Rodriguez, Sabine Herblot, Pierre Thibault, John Strouboulis, Paul-Henri Romeo and Trang Hoang. ETO2 coordinates cellular proliferation and differentiation during erythropoiesis. EMBO J., 25;25(2): 357-366, 2006.
- Sabine Herblot, Ann-Muriel Steff, Patrice Hugo, Peter D. Aplan, Trang Hoang : SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-TCRa chain expression. Nature Immunology, 1: 138-144, 2000.