David A. Williams, MD
Chief, Division of Hematology/Oncology
|Academic Title||Leland Fikes Professor of Pediatrics|
|David A. Williams|
300 Longwood Avenue
Boston, MA 02115
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.
The major interest of the Williams laboratory is focused on the biology of hematopoietic stem cells. This work has focused on understanding the interaction of hematopoietic stem cells with the bone marrow and abnormalities of these interactions which are associated with leukemia.
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. Current work is dissecting the upstream activators and downstream effectors of Rho GTPase in hematopoietic stem cells.
The laboratory has demonstrated that Rac GTPases are key regulators of the engraftment and mobilization functions of hematopoietic stem cells. Increasing focus has been on the dysregulated function of these key molecular switches in leukemia. Recent data from the Williams’ laboratory implicates both Rac and Rho in acute and chronic leukemias and current efforts include development of new inhibitors of these molecular targets and validation studies of these molecules in leukemia model systems. In addition, this basic work has helped to define the molecular abnormalities in two rare immunodeficiency diseases, Leukocyte Adhesion Deficiency Type IV (due to RAC2 mutations) and Epidermodysplasia Verruciformis (due to mutations in RHOH).
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 and lentivirus vectors.
Dr. Williams is serving as sponsor investigator for a number of human gene therapy trials at CHB, including in SCID-X1, Wiskott-Aldrich Disease, Childhood Cerebral Adrenoleukodystropy and a planned trial in sickle cell disease targeting the transcription factor BCL11a.
Major goals of research
- 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.
Grants, Awards, and Honors
Dr. Williams has won numerous prestigious awards for his research, including: the Dameshek Award and the Frank Oski Award of the American Society of Hematology for research in hematology; the Donald Metcalf Award from the International Society for Hematology and Stem Cells for contributions to the field; the E. Mead Johnson Award of the Society for Pediatric Research for research in pediatrics and most recently the Outstanding Achievement Award of the American Society of Gene and Cell Therapy (2011). He was an Investigator of the Howard Hughes Medical Institute for 16 years and is a member of the National Academy of Sciences Institute of Medicine. He has been continuously funded by the National Institutes of Health since 1986. Dr. Williams has multiple patents, several of which have been licensed to pharmaceutical and biotechnology.
- Roberts A, Kim C, Zhen L, Lowe J, Kapur R, Petryniak B, Spaetti A, Pollock J, Borneo J, Bradford GB, Atkinson SJ, Dinauer MC, Williams DA: Deficiency of the Hematopoietic cell-specific Rho-family GTPase, Rac2, is characterized by multiple abnormalities in neutrophil function and impaired host defense. Immunity 10:183-196, 1999.
- Williams DA, Tao W, Yang F, Kim C, Gu Y, Mansfield P, Levine JE, Petryniak B, Derrow CW, Harris C, Jia B, Ambruso D, Lowe J, Atkinson SJ, Dinauer MC, Boxer L: A dominant negative mutation of the hematopoietic-specific RhoGTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 96(5):1646-1654, 2000.
- 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.
- Walmsley MJ, Steen KT, Reynolds LF, Smith SH, Ruf S, Mathoit A, Vanes L, Williams DA, Cancro MP, Tybulewicz VJ: Rac1 and Rac2 GTPases play criticial roles in B cell development and signaling. Science 302: 459-462, 2003.
- Filippi MD, Harris CE, Meller J, Gu Y, Zheng Y, Williams DA: Unique intracellular localization of Rac2 specifies superoxide generation, actin polarity and chemotaxis in neutrophils. Nature Immunology 5: 744-751, 2004.
- 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.
- Ghiaur, G, Lee A, Bailey J, Cancelas J, Zheng Y, Williams DA: Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment In Vivo. Blood 108 (6):2087-94, 2006.
- Gu Y, Chae H, Siefring JE, Jasti AC, Hildeman DA, Williams DA: "RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development." Nature Immunology 7(11): 1182-1190, 2006.
- Kawshima T., Yausushi N., Bao Y., Moon Y., Tonozuka Y., Minoshima Y., Hatori T., Tsuchiya A., Kiyono M., Nosaka T., Nakajima H., Williams DA., Kitamura T: Rac1 and a GTPase activating protein MgcRacGAP are required for nuclear translocation of STAT transcription factors. Journal of Cell Biology 175 (6): 937-946, 2006.
- 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.
- Ghiaur G, Ferkowicz MJ, Milsom MD, Bailey J, Cancelas JA, Yoder MC, Williams DA: Rac1 is essential for intra-embryonic hematopoiesis and for the initial seeding of fetal liver with definitive hematopoietic progenitor cells. Blood, 111( 7): 3313-3321, 2008.
- Wu X, Xiaolin T, Joeng KS, Hilton MJ, Williams DA, Long F: "Rac1 activation and subsequent of ?-catenin phosphorylation controls nuclear localization of β-catenin during canonical signaling." Cell, 133:340-353, 2008.
- Milsom M, Schiedlmeier B, Bailey J, MiOk K, Li D, Jansen M, Ali A, Kirby M, Baum C, Fairbairn L and Williams DA: "Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor- ? on Fanconi anemia hematopoietic stem and progenitor cells", Blood, 113(21): 5111-5120, 2009.
- Sanchez-Aguilera A, Rattman I, Drew DZ, Muller L, Summey V, Lucas DM, Byrd JC, Croce CM, Gu Y, Cancelas JA, Johnston P, Moritz T, Williams DA: "Involvement of RhoH GTPase in the Development of B-Cell Chronic Lymphocytic Leukemia." Leukemia, 24(1): 97-104, 2009.
- Chae D, Siefring J, Hildeman D, Gu Y and Williams DA: “RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling.” PLoS ONE, 5(11): 2010, e13970.
- 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.
- Croke M, Ross FP, Korhonen M, Williams DA, Zou W, Teitelbaum SL: “Rac Deletion in Osteoclasts Causes Severe Osteopetrosis.” J. Cell Sci.,124(Pt. 2):3811-21, 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.
- Mizukawa B, Wei J, Shresth M, Wunderlich M, Chou FS, Griesinger A, Harris CE, Kumar A, Zheng Y, Williams DA, Mulloy JC: “Inhibition of Rac GTPase signaling and downstream pro-survival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia.” Blood, 118(19):5235-45, 2011.
- Mondal S, Ghosh-Roy SG, Loison F, Li Y, Jia Y, Harris C, Williams DA, Luo HR: “PTEN negatively regulates engulfment of apoptotic cells by modulating activation of Rac GTPase.” J. Immunol, 187(11):5783-94.