DF/HCC Program Affiliation

Lymphoma and Myeloma
Cutaneous Oncology and Melanoma

Research Abstract

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.

Publications

• Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD.Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia.Proc Natl Acad Sci U S A 2007 Mar 27;104(13):5431-6.
  17374716
• Schreiber TH, Shinder V, Cain DW, Alon R, Sackstein R.Shear flow-dependent integration of apical and subendothelial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigm.Blood 2007 Feb 15;109(4):1381-6.
  17038526
• Dagia NM, Gadhoum SZ, Knoblauch CA, Spencer JA, Zamiri P, Lin CP, Sackstein R.G-CSF induces E-selectin ligand expression on human myeloid cells.Nat Med 2006 Oct;12(10):1185-90.
  16980970
• Sackstein R, Fuhlbrigge R.The blot rolling assay: a method for identifying adhesion molecules mediating binding under shear conditions.Methods Mol Biol 2006;341:217-26.
  16799202
• Burdick MM, Chu JT, Godar S, Sackstein R.HCELL is the major E- and L-selectin ligand expressed on LS174T colon carcinoma cells.J Biol Chem 2006 May 19;281(20):13899-905.
  16565092
• Sackstein R.A Revision of Billingham's Tenets: The Central Role of Lymphocyte Migration in Acute Graft-versus-Host Disease.Biol Blood Marrow Transplant 2006 Jan;12(1S1):2-8.
  16399577
• Sackstein R.The lymphocyte homing receptors: gatekeepers of the multistep paradigm.Curr Opin Hematol 2005 Nov;12(6):444-50.
  16217160
• Hanley WD, Burdick MM, Konstantopoulos K, Sackstein R.CD44 on LS174T colon carcinoma cells possesses E-selectin ligand activity.Cancer Res 2005 Jul 1;65(13):5812-7.
  15994957
• Sackstein R.The bone marrow is akin to skin: HCELL and the biology of hematopoietic stem cell homing.J Invest Dermatol 2004 May;122(5):1061-9.
  15140204
• Dimitroff CJ, Kupper TS, Sackstein R.Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen.J Clin Invest 2003 Oct;112(7):1008-18.
  14523038
• Milinkovic M, Antin JH, Hergrueter CA, Underhill CB, Sackstein R.CD44-hyaluronic acid interactions mediate shear-resistant binding of lymphocytes to dermal endothelium in acute cutaneous GVHD.Blood 2004 Jan 15;103(2):740-2.
  14504094
• Dimitroff CJ, Bernacki RJ, Sackstein R.Glycosylation-dependent inhibition of cutaneous lymphocyte-associated antigen expression: implications in modulating lymphocyte migration to skin.Blood 2003 Jan 15;101(2):602-10.
  12393521
• Sackstein R, Messina JL, Elfenbein GJ.In vitro adherence of lymphocytes to dermal endothelium under shear stress: implications in pathobiology and steroid therapy of acute cutaneous GVHD.Blood 2003 Jan 15;101(2):771-8.
  12393384
• Fuhlbrigge RC, King SL, Dimitroff CJ, Kupper TS, Sackstein R.Direct real-time observation of E- and P-selectin-mediated rolling on cutaneous lymphocyte-associated antigen immobilized on Western blots.J Immunol 2002 Jun 1;168(11):5645-51.
  12023362
• Dimitroff CJ, Lee JY, Rafii S, Fuhlbrigge RC, Sackstein R.CD44 is a major E-selectin ligand on human hematopoietic progenitor cells.J Cell Biol 2001 Jun 11;153(6):1277-86.
  11402070
• Dimitroff CJ, Lee JY, Fuhlbrigge RC, Sackstein R.A distinct glycoform of CD44 is an L-selectin ligand on human hematopoietic cells.Proc Natl Acad Sci U S A 2000 Dec 5;97(25):13841-6.
  11095749