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.

Tôt en carrière, Trang Hoang s’est intéressée à la leucémie et aux cellules souches. Elle a longtemps dirigé les programmes (interdisciplinaires et multidisciplinaires) de maîtrise et de doctorat en biologie moléculaire, offerts à l’Université de Montréal (UdeM). Cette chercheuse de renom a découvert les cellules anormales qui causent certaines leucémies aigües lymphoblastiques (cancers fréquents chez les enfants).

En 2003, elle a contribué étroitement à fonder, à Montréal, l’Institut de recherche en immunologie et en cancérologie; elle y a aussitôt pris la tête du laboratoire de recherche sur l’hématopoïèse et la leucémie. La même année, elle a commencé à enseigner au Département de pharmacologie et physiologie de l’UdeM.

Publications récentes

• Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation. Chennupati V, Veiga DF, Maslowski KM, Andina N, Tardivel A, Yu EC, Stilinovic M, Simillion C, Duchosal MA, Quadroni M, Roberts I, Sankaran VG, MacDonald HR, Fasel N, Angelillo-Scherrer A, Schneider P, Hoang T, Allam R. J Clin Invest. 2018 Apr 2;128(4):1597-1614. doi: 10.1172/JCI94956. Epub 2018 Mar 19. PMID: 29408805

• Evolution of AF6-RAS association and its implications in mixed-lineage leukemia. Smith MJ, Ottoni E, Ishiyama N, Goudreault M, Haman A, Meyer C, Tucholska M, Gasmi-Seabrook G, Menezes S, Laister RC, Minden MD, Marschalek R, Gingras AC, Hoang T, Ikura M. Nat Commun. 2017 Oct 23;8(1):1099. doi: 10.1038/s41467-017-01326-5. PMID: 29062045

• Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylate Gab2 To Promote a Negative-Feedback Loop That Attenuates Phosphoinositide 3-Kinase/Akt Signaling. Zhang X, Lavoie G, Méant A, Aubert L, Cargnello M, Haman A, Hoang T, Roux PP. Mol Cell Biol. 2017 Mar 17;37(7). pii: e00357-16. doi: 10.1128/MCB.00357-16. Print 2017 Apr 1. PMID: 28096188

• 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-T alpha chain expression . Nature Immunology , 1 : 138-144, 2000 (News and Views by Cornelius Murre. Intertwining proteins in thymocyte development and cancer. Nature Immunology, 1: 97-98, 2000. Nature Immunology

• Cornelis F. Calkhoven , Christine Müller, Richard Martin, Goradz Krosl, Trang Hoang , and Achim Leutz. Translational control of SCL-isoform expression in hematopoietic lineage choice. Genes Dev. Apr 15;17(8):959-64, 2003. Genes & Development — PDF Version: Calkhoven et al. 17 (8):959

• Rachid Lahlil, Éric Lécuyer, Sabine Herblot and Trang Hoang. SCL Assembles a Multifactorial Complex That Determines Glycophorin A Expression. Mol.Cell Biol 2004.  24(4):1439-52. MCB — PDF Version: Lahlil et al. 24 (4):1439

• The LMO2 oncogene regulates DNA replication in hematopoietic cellsSincennes MC, Humbert M, Grondin B, Lisi V, Veiga DF, Haman A, Cazaux C, Mashtalir N, Affar el B, Verreault A, Hoang T. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1393-8. PMID: 26764384

• SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells. Gerby B, Tremblay CS, Tremblay M, Rojas-Sutterlin S, Herblot S, Hébert J, Sauvageau G, Lemieux S, Lécuyer E, Veiga DF, Hoang T. PLoS Genet. 2014 Dec 18;10(12):e1004768. PMID: 25522233

• Genetic interaction between Kit and Scl. Lacombe J, Krosl G, Tremblay M, Gerby B, Martin R, Aplan PD, Lemieux S, Hoang T. Blood. 2013 Aug 15;122(7):1150-61. PMID: 23836559

•  Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenesTremblay M, Tremblay CS, Herblot S, Aplan PD, Hébert J, Perreault C, Hoang T. Genes Dev. 2010 Jun 1;24(11):1093-105. PMID: 20516195