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Ivan Maillard , M.D., Ph.D.
Associate Professor of Internal Medicine
Associate Professor of Cell and Developmental Biology
Center for Stem Cell Biology, Life Sciences Institute
Division of Hematology-Oncology, Department of Medicine
imaillar@umich.edu


Research Interests:

Notch signaling, hematopoietic stem cells, T cell differentiation and homeostasis, bone marrow transplantation, alloimmunity, autoimmunity

 

Research Activity

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.

 

Representative Publications

Sandy AR, Stoolman J, Malott K, Pongtornpipat P, Segal BM, Maillard I. Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol, 191(4): 1606-1613, 2013.

Sandy AR, Chung C, Toubai T, Shan GT, Tran IT, Friedman A, Blackwell TS, Reddy P, King PD, Maillard I. T cell-specific Notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells. J Immunol, 190(11): 5818-5828, 2013.

Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J, Shan GT, Radojcic V, Friedman A, Gridley T, Shelton A, Reddy P, Samuelson LC, Yan M, Siebel CW, Maillard I. Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest, 123(4): 1590-1604, 2013.

Chung J, Maillard I. Notch signaling in alloreactive T cell immunity. Current Topics in Microbiology and Immunology, 360: 135-150, 2012.

Tan J, Jones M, Koseki H, Nakayama M, Muntean A, Maillard I, Hess JL. CBX8, a Polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell, 20(5): 563-575, 2011.

Toubai T, Sun Y, Tawara I, Friedman A, Liu C, Evers R, Nieves E, Chockley P, Maillard I, Winandy S, Reddy P. Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease. Blood, 118(1): 192-204, 2011.

Zhang Y, Sandy AR, Wang J, Shan GT, Radojcic V, Tran I, Friedman A, Kato K, He S, Cui S, Hexner E, Frank D, Emerson SG, Pear WS, Maillard I. Notch signaling is a critical regulator of allogeneic CD4+ T cell responses mediating graft-versus-host disease. Blood, 117(1): 299-308, 2011

Jo SY, Granowicz EM, Maillard I, Thomas D, Hess JL. Requirement for Dot1L in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood, 117(18): 4759-68, 2011.

Sandy AR, Maillard I. Notch signaling in the hematopoietic system. Expert Opin Biol Ther Oct;9(11):1383-1398, 2009.

Maillard I, Chen YC, Friedman A, et al. Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood, 113(8): 1661-1669, 2009.

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.

Maillard I., L. Tu, A. Sambandam, Y. Yashiro-Ohtani, J. Millholland, K. Keeshan, O. Shestova, L. Xu, A. Bhandoola and W.S. Pear. The requirement for Notch signaling at the beta selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J. Exp. Med., 203(10): 2239-45, 2006.

Maillard I., B. Schwarz, A. Sambandam, T.Fang, O. Shestova, L. Xu, A. Bhandoola and W.S. Pear. Notch-dependent T lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood, 107(9): 3511-19, 2006.

Maillard I., T. Fang and W.S. Pear. Regulation of lymphoid development, differentiation and function by the Notch pathway. Annu Rev Immunol, 23:945-974, 2005.

Sambandam A.*, I. Maillard*, V.P. Zediak, L. Xu, R.M. Gerstein, J.C. Aster, W.S. Pear and A. Bhandoola. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunology, 6(7):663-70, 2005 (*equal contribution).

Maillard I., A.P. Weng, A.C. Carpenter, C.G. Rodriguez, H. Sai, L. Xu, D. Allman, J.C. Aster, and W.S. Pear. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood, 104(6):1696-702, 2004.

 


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