Robert Sackstein, MD, PhD
Professor, Department of Dermatology, Harvard Medical School
Professor, Department of Medicine, Harvard Medical School
Physician Active Staff, Dermatology and Medicine, Brigham And Women's Hospital
DF/HCC Program AffiliationLymphoma and MyelomaCutaneous Oncology and Melanoma
In early work, our laboratory identified that L-selectin expression is characteristic not only of lymphocytes but also of early hematopoietic progenitor cells, and this observation led us to examine the expression of L-selectin ligands among human bone marrow cells. These studies led to identification of an L-selectin ligand on early hematopoietic progenitor cells that is structurally distinct from L-selectin ligands expressed on endothelial cells. Subsequent biochemical studies from our laboratory revealed that this ligand, now known as Hematopoietic Cell E-/L-selectin Ligand (HCELL), is the most potent naturally-expressed E- and L-selectin ligand in the body. HCELL is a specialized glycoform of CD44 natively expressed exclusively on human hematopoietic stem cells. Through its role as a potent E-selectin ligand, HCELL functions as the "bone marrow homing receptor" that directs hematopoietic stem cell migration into the marrow. Current studies are aimed at elucidating HCELL's role in hematopoiesis and in the regulation of stem cell homing. In addition, HCELL is characteristically expressed on blasts of acute leukemia, and thus we are investigating how HCELL expression is related to leukemogenesis and how expression of this molecule is regulated on normal stem cells and leukemic blasts. In complementary studies, we have developed reagents to program HCELL expression by ex vivo glycan engineering of surface CD44 and we are examining how enforced HCELL expression licenses the delivery of adult stem cells intravascularly for regenerative therapeutics and how it affects leukemogenesis. Another focus of our laboratory is to elucidate the physiology of lymphocyte migration following hematopoietic stem cell transplantation (HSCT). We have obtained evidence that the migration of lymphocytes to lymph nodes post-HSCT is disturbed in part because of disordered regulation of lymphocyte L-selectin gene expression. We are examining the molecular basis of altered L-selectin expression, and, moreover, we are studying how pathologic tissue-specific migration patterns develop post-transplant. In particular, acute graft-versus-host disease (GVHD) following allogeneic HSCT is characterized by the directed migration of alloreactive lymphocytes into three principal target tissues - skin, liver and gut - wherein they mediate tissue destruction. Our laboratory is investigating the adhesion molecules that regulate skin-specific migration of lymphocytes in cutaneous GVHD reactions, in order to elucidate the molecular basis of this process and develop therapeutic agents to treat or prevent cutaneous GVHD. Our overall aim in these studies is to devise novel therapies to eliminate the detrimental GVHD reaction of allogeneic transplantation without disturbing beneficial immune reactions such as the graft-versus-malignancy effect. In other studies, we are investigating the structural biology of key molecules which mediate adhesive interactions that create microenvironmental "niches" for tumor cell proliferation, the adhesion molecules which allow for tumor cell dissemination, and the adhesion molecules that regulate lymphocyte trafficking to sites of tumor. The goal in these studies is to utilize structural information for the rational design of drugs that disrupt adhesion molecules critical for tumor cell growth and metastasis, and that improve immune effector cell infiltration of tumor tissue.
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