Research Interests:

Normal and abnormal human B cell development

Normal B cell precursors and their leukemic counterparts in B cell precursor acute lymphoblastic leukemia (ALL) are poised to undergo different fates, including: survival, proliferation, differentiation, or apoptosis. Our laboratory has parallel interests in investigating the role of the bone marrow microenvironment in regulating the fate of normal and leukemic human B cell precursors. We have established a panel of human B cell precursor ALL cell lines that retain a dependency on human marrow stromal cells for survival and proliferation. These novel cell lines are facilitating the analysis of marrow stromal cell-derived molecules that regulate B cell precursor fates, the signaling pathways in B cell precursors that promote survival, the biochemical basis of cell death that follows loss of marrow stromal cell signaling, and the genetic basis of tumor progression that underlies the evolution of a leukemic clone from a stromal cell-dependent to a stromal cell-independent phenotype.  A related project employs a xenogeneic model system that supports human B-cell development from CD34+ cord blood stem cells using a murine marrow stromal cell microenvironment.  This model has recently been exploited to implicate IL-7 as a replicative signal in human B-cell development.  It is currently being used to characterize: a) the intracellular signaling pathways activated by IL-7, b) the role of marrow microenvironment-derived cytokines in cooperating with IL-7, and c) the outcome of modifying gene expression in B cell precursors (using retroviral vectors and RNA interference) on their developmental fate.  The long-term goal is to elucidate the biochemical basis that distinguishes survival and death in developing B-lineage cells, and perturbations in B-lineage ALL that suppress cell death and promote clonal expansion.

Selected Recent Publications:

• Hermanson, D., S.N Addo, A. Bajer, J. Marchant, S.G.K. Das, B. Srinivasan, F. Al-Mousa, F. Michelangeli, D.D. Thomas, T.W. LeBien*, and C. Xing*. 2009. Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria. Molecular Pharmacol. 76:667-678 (*co-senior authors).

• Xue, X., X. Huang, S.E. Nodland, L. Mates, L. Ma, Z. Izsvak, Z. Ivics, T.W. LeBien, R.S. McIvor, J.E. Wagner, and X. Zhou. 2009. Stable gene transfer and expression in cord blood-derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system. Blood 114:1319-1330 (editorialized)

• Johnson, S.E., N. Shah, A. Bajer, and T.W. LeBien. 2008. IL-7 activates the PI3K/AKT pathway in normal human thymocytes but not normal human B-cell precursors. J. Immunol. 180:8109-8117.

• LeBien, T.W. and T.F. Tedder. 2008. B-lymphocytes: how they develop and function. Blood 112:1570-1580.

• LeBien, T.W. 2006. Battling bone marrow B-lineage cells. Blood 108:1120.

• Johnson SE, Shah N, Panoskaltsis-Mortari A, and LeBien TW.  2005. Murine and human IL-7 activate STAT5 and induce proliferation of normal human pro-B cells.  J. Immunol. 175:7325-7331.

Last modified on: September 30, 2009