Fundamental to understanding blood cell homeostasis and disease, is the identification and characterization of regulatory molecules that control blood cell genesis. Our research is focused on understanding the biological processes involved in early B lymphocyte development. We are learning how the B cell differentiation program is activated in hematopoietic progenitors, identifying which components of the pathway are involved in B cell homeostasis, which are subject to systemic regulation, and investigating the role of one early B lineage regulator in establishing a differentiation impaired premalignant state. Our goal is to gain a better understanding of normal B cell development which will aid in the identification of new molecular targets for therapeutic intervention in B cell malignancies or immunodeficiencies.

Current Research Topics

Considerable progress has been made in understanding the generation of naïve B cells from committed B cell precursors, but little is known concerning how this process begins. The receptor tyrosine kinase Flk2/Flt3 plays a critical role in early hematopoiesis and dysregulated expression or function results in severe deficiencies in bone marrow B cell precursors. We are currently investigating the molecular requirements for activation of the Flk2/Flt3 gene as well as those involved in silencing the gene during lineage specific differentiation. Another related project is focused on understanding the role of Flk2/Flt3 signaling in B cell fate specification, examining the stages of B cell development that are dependent on Flk2/Flt3 and elucidating the specific role of Flk2/Flt3 in those stages.

Hematopoietic stem cells and their immediate progeny display low levels of mixed lineage patterns of gene expression reflecting their developmentally primed state. The early program of B cell development is dependent on the combinatorial activities of two B lineage determinants, E2A and EBF. Specific target genes and differentiation-related events regulated by E2A and EBF during B cell fate specification are unclear and currently under investigation. Multipotential EBF-/- cell lines have been generated and are being utilized to investigate the role(s) of these and other key regulatory molecules in regulation of the early program of B lineage gene expression, initiation of antigen receptor gene recombination, and silencing alternative or inhibitory gene products that impair B cell differentiation and may contribute to the establishment of a premalignant state.