Ivan Maillard , M.D., Ph.D.
Assistant Professor of Internal Medicine
Assistant 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, blood-forming stem cells, T cell differentiation and homeostasis, bone marrow and hematopoietic stem cell transplantation, 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) Investigate the homeostasis of blood-forming stem cells in situations of hematopoietic stress; 3) Explore the role of Trithorax family members in the epigenetic regulation of hematopoiesis.

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 epigenetic regulators of the Trithorax family in hematopoietic stem cell homeostasis. We started this project through the study of menin, a protein encoded by the Men1 tumor suppressor gene, in the regulation of hematopoietic stem cell homeostasis. Menin is a nuclear protein that functions as a cofactor for the Mixed Lineage Leukemia (Mll) gene product, a mammalian homologue of Drosophila Trithorax that acts as a Histone 3 Lysine 4 (H3K4) methyltransferase in the epigenetic regulation of transcription. We have discovered that menin is largely dispensable to support hematopoiesis in steady-state conditions, but becomes absolutely essential for hematopoietic stem cell function in situations of hematopoietic stress, such as after bone marrow transplantation. We are currently looking at the consequences of menin loss on cell cycle regulation, survival and differentiation in hematopoietic stem cells.

In a related project, we are investigating the interaction of other histone methyltransferases with menin and MLL. Through recent work 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 newly identified H3K4 methyltransferase activity in mammalian cells. To investigate the role of Ash1L in vivo, we studied mice with decreased Ash1L activity as a result of a gene trap strategy. These mice displayed reduced viability, growth retardation, decreased male fertility and female infertility (Brinkmeier and Camper, unbublished results). In the bone marrow, numbers of long-term hematopoietic stem cells decreased dramatically during post-natal life. This resulted in near complete exhaustion of the stem cell pool at five weeks of age in Ash1L-deficient mice. Transplantation of fetal hematopoietic progenitors revealed a profound cell-autonomous defect in stem cell function. In addition, early defects in lymphoid development were apparent. Our findings reveal a critical non-redundant role for Ash1L in the maintenance of adult blood-forming stem cells. We propose 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, CFO member), 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. We have discovered a major function for the shelterin member Tpp1/Acd in hematopoietic stem cell homeostasis. Future work in this project will investigate the mechanisms of Tpp1/Acd action in the hematopoietic system and the consequences of its loss on stem cell homeostasis.

Representative Recent Publications

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.

Hosoya T, Maillard I, Engel JD. From the cradle to the grave: activities of GATA-3 throughout T cell development and differentiation. Immunol Rev, 238(1): 110-25, 2010.

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.

Wu L*, Maillard I*, Nakamura M, Pear WS, Griffin JD. The transcriptional co-activator Maml1 is required for Notch2-mediated marginal zone B cell development. Blood, 110(10):3618-3623, 2007 (*equal contribution ).

I. Maillard and W.S. Pear. Keeping a tight leash on Notch. Science, 316:840-842, 2007.

L. Talebian, Z. Li, Y. Guo, J. Gaudet, M.E. Speck, D. Sugiyama, P. Kaur, W.S. Pear, I. Maillard* and N.A. Speck*. T lymphoid, megacaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage. Blood (Plenary paper), 109(1):11-21, 2007 (*corresponding authors).

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.

Tu L., T.C. Fang, D. Artis, O. Shestova, S.E. Pross, I. Maillard and W.S. Pear. Notch signaling is an important regulator of type 2 immunity. J. Exp. Med., 202(8):1037-42, 2005.

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.