Williams Lab Research

The Williams laboratory has many projects studying proteins involved in normal hematopoiesis, leukemia, autoimmune disorders and inflammatory diseases in both the murine models as well as the human system, including direct patient-driven research.

 One project seeks to understand the molecular mechanisms of small GTPases, a family of proteins that regulate various cellular processes such as signal transduction, cytoskeleton organization, and intracellular trafficking. We focus on how small GTPases control the development and function of blood cells in health and disease. Specifically, we investigate how these small GTPases modulate the fate and behavior of hematopoietic stem cells. We also study their role in hematologic malignancies such as leukemia, and autoimmune disorders such as lupus. We believe that studying the function of GTPases in these contexts might pave the way for novel therapeutic interventions.

 In a related project we are studying Septins, a group of GTPase proteins which are now considered the fourth structural element of the cytoskeleton. They are one of the most common binding partners of MLL to form fusion proteins which are related to myeloid malignancies in both children and adults. Our laboratory focuses on Septin-6 family proteins and their role in hematopoiesis. One of the projects is focused on point mutations in the SEPTIN6 gene which we and collaborators discovered in two children with congenital neutropenia and their association with pediatric myelodysplastic syndrome. In this project we are studying how acquisition of de novo mutations in the SEPTIN6 gene leads to deleterious effects on engrafting hematopoietic stem cells via gain of novel functions.  Another project is based on the unique and overlapping role of Septin 6 family proteins in murine hematopoiesis. This project focuses on possible redundancies in hematopoietic function within the Septin 6 family.  This project began from studying a patient Dr. Williams cared for with a H/O fellow in the Hematology Clinic at BCH. This represents a long-time focus in the Williams laboratory of patient-driven investigations with the laboratory work defining the molecular etiology of three human diseases due to mutations in RAC2, RHOH and SEPTIN6.

We have two ongoing gene therapy projects.  The first is studying hemoglobinopathies mainly sickle cell disease. We have been dedicated to engineering innovative gene therapy methods and conducting preclinical trials to explore their efficacy in the treatment of sickle cell disease. These studies have led to a successful phase 1 trial in humans and now an NIH-funded phase 2 national multi-center trial which we lead and continue biological science of specimens from the trial. We also continue to improve the current vector and study methods to improve cell manufacturing in the laboratory.  The aim is to develop effective treatments that correct the sickle cell disease phenotype, thereby offering patients a potential cure or significant symptom relief.

Lastly we have been studying mutations in the IL-10 gene or its receptor and how these mutations lead to life threatening Very Early Onset-Inflammatory Bowel Disease (VEO-IBD) usually within the first months of life. In these cases, allogeneic stem cell transplant (HSCT) is the only curative option, leading to prolonged disease remission and survival. Gene therapy represents a valid therapeutic alternative, through autologous transplantation of genetically corrected hematopoietic stem and progenitor cells (HSPCs). We are developing a lentiviral vector-based gene therapy approach for congenital defects of the murine IL-10 receptor beta chain (mIl10rb) and studying the role of IL-10 in normal hematopoiesis.  Genetic correction of mIl10rb knock-out HSPCs by lentiviral vectors restores responsiveness to IL-10 and leads to amelioration of IBD phenotype in a mouse model.