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.

Segel GB, Woodlock TJ, Xu J, Li L, Felgar RE, Ryan DH, Lichtman MA, Wang N. Early gene activation in chronic leukemic B lymphocytes induced toward a plasma cell phenotype. Blood Cells Mol Dis. 30:277-87, 2003.

Phatak PD, Ryan DH, Cappuccio J, Oakes D, Braggins C, Provenzano K, Eberly S, Sham RL. Prevalence and penetrance of HFE mutations in 4865 unselected primary care patients. Blood Cells Mol Dis. 2002 Jul-Aug;29(1):41-7.

Pugh-Bernard AE, Silverman GJ, Cappione AJ, Villano ME, Ryan DH, Insel RA, Sanz I. Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J Clin Invest. 108:1061-70, 2001.

Rowe JM, Rapoport AP, Ryan DH, Nilsson BI, Duerst RE, Packman CH, Abboud CN, DiPersio JF, Linder T, Wang N, Simonsson B, Liesveld JL. Treatment of chronic myelogenous leukemia with autologous bone marrow transplantation followed by roquinimex. Bone Marrow Transplant. 24:1057-63, 1999.

Ryan DH, Crowther MA, Ginsberg JS, Francis CW. Relation of factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery. Ann Intern Med 128:270-6, 1998.

Hu BT, Lee SC, Marin E, Ryan DH, Insel RA. Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J Immunol 159:1068-71, 1997.

Ryan DH, Nuccie BL, Ritterman I, Liesveld JL, Abboud CN, Insel RA. Expression of IL-7 receptor by lineage- negative early human bone marrow progenitors with enhanced lymphoid proliferative potential and B lineage differentiation capacity. Blood 89:929-940, 1997.

Tang J, Nuccie BL, Ritterman I, Liesveld JL, Abboud CN, Ryan DH. Transforming growth factor (TGF-beta) downregulates stromal IL-7 secretion and inhibits proliferation of human B cell precursors. J Immunol 159: 117-125, 1997.

Ryan DH, Tang J. Regulation of human B cell lymphopoiesis by adhesion molecules and cytokines. Leuk Lymphoma. 1995 May;17(5-6):375-89.