Ivan Maillard , M.D., Ph.D.
Notch signaling, hematopoietic stem cells, T cell differentiation and homeostasis, bone marrow transplantation, alloimmunity, autoimmunity
Our research is devoted to the following main topics: 1) Understand the role of Notch signaling in the regulation of T cell homeostasis and differentiation, particularly in the setting of alloimmunity and autoimmune disorders; 2) Explore the role of Trithorax family members and other epigenetic regulators in hematopoiesis; 3) Study the role of the shelterin protein Acd/Tpp1 in hematopoietic stem cell homeostasis.
In a first project, we are interested in the regulation of mature T cell homeostasis and differentiation by Notch signaling. Using several genetic models of Notch inactivation, we are investigating the molecular and cellular mechanisms underlying the activity of Notch signaling in allogeneic T cell responses (T cell responses against foreign tissue antigens). Our findings indicate that Notch behaves as a novel and potent master regulator of T cell function in several mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. We are currently investigating the molecular mechanisms of this effect and its potential therapeutic applications in GVHD, organ rejection and other T cell-mediated immune disorders. As a major research effort for the next 3-5 years, we will study the role of individual Notch receptors and ligands in T cell alloimmunity using a combination of genetic and biochemical approaches. We are also investigating the role of Notch signaling in models of autoimmunity, including Experimental Autoimmune Encephalomyelitis.
In a second project, we are investigating the role of Trithorax family histone methyltransferases in the regulation of hematopoietic stem cell function. In collaboration with Dr. Sally Camper (Human Genetics), we have discovered a novel essential hematopoietic function for Ash1l, a homologue of the fly Absent, small and homeotic discs 1 (Ash1) gene with putative H3K36 methyltransferase activity in mammalian cells. To investigate the role of Ash1L in vivo, we are studying mice with decreased Ash1l activity as a result of a gene trap strategy. Emergence and expansion of Ash1l-deficient fetal/neonatal HSCs were preserved, but young adult HSCs were profoundly depleted. Ash1l-deficient adult HSCs had markedly decreased quiescence, reduced Cdkn1b/1c expressionandfailed to establish long-term trilineage bone marrow hematopoiesis after transplantation to irradiated recipients. Wild-type HSCs could efficiently engraft unirradiated Ash1l-deficient recipients, indicating increased availability of functional HSC niches in these mice. Ash1l deficiency decreased expression of multiple Hox genes in hematopoietic progenitors. Ash1l cooperated functionally with Mixed lineage leukemia 1 (Mll1), as combined Ash1l/Mll1 but not isolated Ash1l or Mll1 deficiency induced overt hematopoietic failure. Our results uncover a Trithorax group gene network that controls quiescence, niche occupancy and self-renewal potential in adult HSCs. We will continue to investigate in detail the function of Ash1l in hematopoietic stem cells, study its interaction with MLL and explore its role in leukemia stem cells.
Finally, in collaboration with Dr. Catherine Keegan (Pediatrics), we are exploring the function of the “shelterin” complex in blood-forming stem cells. The shelterin complex is group of proteins that together is responsible to prevent the recognition of telomeric structures by the DNA damage machinery, while contributing to telomerase recruitment. We have discovered a major function for the shelterin member Acd/Tpp1 in hematopoietic stem cell homeostasis. Future work in this project will investigate the mechanisms of Acd/Tpp1 action in the hematopoietic system, the consequences of its loss on stem cell homeostasis, and its role in the recruitment of telomerase.
Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC, Bhandoola A, Radtke F, Pear WS. Canonical Notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell, 2(4):356-366, 2008.