The laboratory focuses 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 adhesion, migration, 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 includes dissecting the upstream activators and downstream effectors of Rac GTPases 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 RhoH in acute and chronic leukemia’s 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 Boston Children’s Hospital, including X-Linked Severe Combined Immunodeficiency (SCID-X1), Wiskott-Aldrich Disease, Childhood Cerebral Adrenoleukodystrophy, and a trial in sickle cell disease targeting the transcription factor BCL11a.