Daniel H. Ryan, M.D.

We are interested in the molecular events determining B lymphoid lineage commitment and early differentiation of B cell progenitors. Insight into the regulation of B cell development can be applied to studies of childhood lymphoblastic leukemia, a neoplasm derived from an early B lymphoid progenitor which cannot properly commit and/or differentiate into a mature B cell.

Signals for human B cell development are incompletely understood, largely due to difficulties in culturing normal human B cell progenitors. Using a bone marrow stromal dependent culture system, we have identified colony forming human lymphoid progenitors in a very early bone marrow population (CD34+/CD19-/IL-7 receptor -) which expresses early myeloid as well as lymphoid markers, and may therefore represent cells engaged in the earliest steps of commitment to two of the major hematopoietic lineages, lymphoid and myeloid. This experimental system can be used to define critical molecular events determining the commitment of early human hematopoietic progenitors to B lymphoid differentiation.

The goal of my research is to characterize the signals for lineage commitment and B lineage differentiation of these early human lymphoid progenitors. Efforts focus on analysis of immunoglobulin gene rearrangements of individual progenitors as an indicator of early B lineage commitment using advanced cell sorting and micromanipulation techniques, and transfer of B lineage specific regulatory genes directly into normal human hematopoietic progenitors to assess their contribution to B lineage commitment and development.