David A. Williams
Chief of the Division of Hematology/Oncology
Director of Translational Research for Children's Hospital Boston
Associate Chairman, Department of Pediatric Oncology
Karp Building, Room 08125.3
300 Longwood Ave.
Boston, MA 02115
Visit my lab page here.
Research in the Williams' laboratory focuses on understanding the biology of the hematopoietic stem cells, including development of gene transfer methods for application in the treatment of severe genetic diseases of the blood system by gene therapy. Currently the laboratory is focusing on analysis of the function of members of the Rho GTPase family, specifically Rac and RhoH in blood cell development and function. Rho GTPases are members of the Ras superfamily and act as molecular switches to control multiple cell processes, such as migration, phagocytosis, cell cycle progression, and apoptosis via activation of multiple kinase pathways. Using gene targeted transgenic mice, and a variety of specialized bone marrow culture methods, Dr. Williams' laboratory is defining the essential roles of Rho GTPases in blood cell functions, particularly in response to integrin ligation and activation of chemokine and cytokine receptors. The laboratory has recently demonstrated that Rac GTPases are key regulators of the engraftment and mobilization functions of hematopoietic stem cells. In addition, two human diseases have been identified with causal RhoGTPase mutations by the Williams laboratory, Leukocyte Adhesion Deficiency type IV (RAC2 dominant negative mutation) and Eperdermodysplasia verruciformis (RHOH mutation). Increasing focus has been on the dysregulated function of these key molecular switches in leukemia, including screening for small molecule inhibitors of the pathway for drug development. Much of the basic information derived from these studies is also being applied to improve the methods of gene transfer into hematopoietic stem cells using retrovirus, foamy virus, and lentivirus vectors and with current human trials ongoing in severe combined immunodeficiency, Wiskott-Aldrich syndrome and adrenoleukodystrophy. Pre-clinical gene therapy work is ongoing in Fanconi anemia and sickle cell disease.
Our current research has three major goals:
To further understand the role Rho GTPases as key regulatory switches that control stem cell adhesion, migration and survival/proliferation.
Continue to develop and advance the use viral vectors for gene transfer into hematopoietic stem cells with the purpose of advancing clinical gene therapy trials.
To advance the translation of basic research into novel therapeutic applications.
Gu Y , Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, Harris CE, Lee AW, Prabhakar R, Atkinson SJ, Kwiatkowski DJ, Williams DA: Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302: 445-449, 2003.
Cancelas J, Prabhakar R, Lee A, Zheng Y, Williams, DA: Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nature Medicine 11 (8): 886-891, 2005
Thomas EK, Harris CE, Druker BJ, Zheng Y, Cancelas JA, Williams DA: “Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR/ABL-induced myeloproliferative disease. Cancer Cell, 12: 467-478, 2007.
Sanchez-Aguilera A, Lee YJ, Lo Celso C, Ferraro F, Brumme K, Mondal S, Kim C, Dorrance A, Lou HR, Scadden DT, Williams DA: “Vav1 regulates perivascular homing and bone marrow retention of hematopoietic stem and progenitor cells.” Proc. Natl. Acad. Sci., USA, 108(23):9607-12, 2011.
Lane SW, Wang YJ, Lo Celso C, Ragu C, Bullinger L, Sykes SM, Ferraro F, Shterental S, Lin CP, Gilliland DG, Scadden DT, Armstrong SA, Williams DA: “Differential niche and Wnt requirements during acute myeloid leukemia progression.” Blood, 118(10):2849-56, 2011.
Lane SW, DeVita S, Kamaran R, Milsom MD, Dorrance AM, Louis L, Bouzsein ML, Williams DA: “Rac signaling in osteoblastic progenitor cells is required for normal bone development but is dispensable for hematopoietic development.” Blood, 119(3): 736-44, 2012.
Mueller LUW, Milsom MD, Harris CE, Vyas R, Brumme KM, Parmar K, Moreau LA, Schambach A, Park IH, London WB, Strait K, Schlaeger Th, DeVine AL, D’AndreaA, Daley GQ, Williams DA: “Overcoming resistance to reprogramming of fanconi anemia cells.” Blood 2012; 119(23): 5449-5457.*Selected for cover and editorial
Troeger A, Johnson AJ, Wood J, Blum WG, Andritsos LA, Byrd JC, Williams DA: “RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans.” Blood, 119(20):4708-18, 2012.
Crequer A, Troeger A, Patin E, Ma CS, Picard C, Pedergnagna V, Fieschi C, Lim A, Gineau L, Krueger J, Abel L, Tangye SG, Orth G*, Williams DA*, Casanova JL*, Jouanguy EP*: “RhoH deficiency: impaired T cell development and function in a kindred with β-papillomavirus infection and epidermodysplasia verruciformis.” In press, Journal of Clinical Investigation, 2012. *Co senior authors
Last Update: 1/3/2013