Infection secondary to neutropenia is a major cause of near-term morbidity and mortality in hematopoietic stem cell transplantation (HSCT) and in cancer therapeutics using myelosuppressive regimens. In each case, the recovery of hematopoiesis, heralded by return of granulocyte production. Is critically dependent on the combinatorial and temporal expression of adhesion molecules that create relevant myelopoietic growth niches within the marrow. Cell surface lactosaminyl glycans, particulariy those bearing terminal sialic acid and fucose modifications, serve as principal effectors, as well as modulators, of a variety of adhesive interactions essential to hematopoiesis. Conspicuously, the expression of these structures within hematopoietic cells of marrow varies distinctly in a stage-specific and lineage-specific manner. We hypothesize that changes In cell surface terminal lactosaminyl glycans help to specify the lineage fate of eariy hematopoietic progenitors, and, commensurately, proliferation and differentiation of these cells. In this project, we seek to define the terminal lactosaminyl glycans expressed on human cells among primitive progenitors, and eariy myeloid and non-myeloid progenitor subsets, obtained from sources relevant to hematopoietic stem cell transplantation (i.e., marrow, G-CSF-mobilized blood, cord blood), and the pertinent protein and/or lipid scaffolds that present these glycans. We will analyze the function(s) of terminal lactosaminyl glycans in licensing adhesive interactions critical to sustaining primitive hematopoietic cells and to driving eariy myelopoietic commitment, and, using a variety of biochemical techniques to remodel their expression, will directly examine how these structures affect hematopoietic processes, particularly myelopoietic proliferation and differentiation. We will also analyze how terminal lactosaminyl glycans mediate supportive interactions between hematopoietic stem cells and marrow stromal cells (""""""""mesenchymal stem cells"""""""", MSCs). These studies will address fundamental Issues regarding the glycobiology of hematopoiesis in humans. It is anticipated that the information obtained will yield transformative strategies to custom-modify expression of key terminal lactosaminyl glycans to achieve the overarching clinical goals of enhancing myelopoietic recovery following myelosuppressive/myeloablatlve chemoradiotherapy, of stimulating hematopoiesis in conditions of marrow failure, and of halting dysregulated myeloproliferation such as in leukemia.

Public Health Relevance

Low levels of white blood cells can result In life-threatening infections. Deficiency of white blood cells is a common complication of cancer therapy and can also occur with bone marrow diseases. Information obtained from this research effort will provide important information on how white blood cells are made, and should pave the way for new treatments to increase white blood cell production when needed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107146-03
Application #
8477243
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$660,136
Indirect Cost
$290,312
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Cheng, Kai; Zhou, Yusen; Neelamegham, Sriram (2017) DrawGlycan-SNFG: a robust tool to render glycans and glycopeptides with fragmentation information. Glycobiology 27:200-205
Dougher, Christopher W L; Buffone Jr, Alexander; Nemeth, Michael J et al. (2017) The blood-borne sialyltransferase ST6Gal-1 is a negative systemic regulator of granulopoiesis. J Leukoc Biol 102:507-516
Lee, Jungmin; Dykstra, Brad; Spencer, Joel A et al. (2017) mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell-derived hematopoietic progenitors. J Clin Invest 127:2433-2437

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