David A. Williams, MD
Leland Fikes Professor of Pediatrics, Department of Pediatrics, Harvard Medical School
Chief, Hematology/Oncology, Boston Children's Hospital
DF/HCC Program AffiliationCancer Cell Biology
Research AbstractPrimary Research Interest
The major interest of our laboratory is focused on the biology of hematopoietic stem cells. The 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. These basic studies contribute to our translational research focus that utilizes hematopoietic stem cells as a target for gene therapy manipulations.
Rho GTPases in normal hematopoiesis
The Rho family of small GTPases are members of the Ras superfamily. The best studied members of this family are Rac1, RhoA and Cdc42. In fibroblasts, Rho activation induces the assembly of filamentous (F)-actin and myosin filaments (stress fibers), while Rac and Cdc42 promote the formation of surface protrusions and ruffling (lamellipodia) and finger-like membrane extensions (filopodia) respectively, both actin containing structures. Using gene-targeted mice, we have shown that Rac plays a critical role in blood cell development and function. Rac activity has been demonstrated to be important for such diverse functions as retention in the bone marrow, long-term engraftment of hematopoietic stem cells and hematopoietic stem cell mobilization. Furthermore, in more committed hematopoietic cells Rac activity is associated with B–lymphocyte development and signaling, granulocyte chemotaxis and superoxide production, migration and degranulation of mast cells, and maturation of TRAP–positive, pro-osteoclasts into multi-nucleated osteoclasts.
Rho GTPases in leukemia
Activation of Rac has previously been shown in Bcr-abl+ chronic myelogenous leukemia (CML). We have utilized gene-targeted mice lacking Rac GTPases to show that Rac is critical for the development and evolution of the myeloproliferative disease associated with expression of the p210 Bcr-abl oncogene. These studies have led to the testing of a small molecule inhibitor of Rac developed by our colleague, Dr. Yi Zheng, on primary CML samples and in the mouse model. These studies are being done in collaboration with Dr. Jose Cancelas, Dr. Brian Druker and Dr. John Byrd. We are also studying the potential role of other GTPases in acute myeloid leukemia and chronic. These studies examine primary samples and leukemia cell lines and are specifically examining the role of Rac and another GTPase, called RhoH, in the leukemia cell phenotype. This work is being done in collaboration with Drs. Yi Gu and John Byrd.