B-lineage cells develop in a programmed fashion that is dependent upon intrinsic patterns of gene expression and extrinsic signals provided by the bone marrow stromal cell contact and soluble growth factors. Our laboratory is interested in genetic pathways that modulate how human B-lineage cells respond to these signals during development. The Notch gene family is an evolutionarily conserved family of receptors that regulates the developmental fate of cells in a variety of development systems. First described in fruit flies, the paradigm for Notch signaling is that in the presence of a Notch signal cells remain in the precursor state, while maintaining full developmental potential. Human B-lineage cells express the Notch-1 receptor throughout B-cell development and express the Notch-2 gene during the pre-B cell receptor (pre-BCR) positive stage of development (1). The biological function of these receptors in developing B-lineage cells is not known. We are presently conducting experiments to determine the function of Notch-1 and Notch-2 during human B-cell development in the context of other well-known B-cell developmental signals such as the IL-7 response, bone marrow stromal cell contact and pre-BCR signaling.
80% of infant acute lymphoblastic leukemia (ALL) bear a rearrangement of the MLL gene. The t(4;11) variant, which fuses MLL to the AF4 gene, is a distinct subset that results in leukemic cells with a predominately pro-B cell phenotype. These cells characteristically exhibit rapid growth, apoptotic resistance and growth factor independence. In addition, MLL/AF4 cells typically have limited B-lineage developmental potential. We have been studying and newly established MLL/AF4 expressing cell line, BLIN-3, that has retained characteristics of a normal B-lineage lineage developmental program; specifically apoptotic sensitivity to bone marrow stromal cell and growth factor withdrawal, Il-7 responsiveness, and DJH to VDJH rearrangement resulting in pre-BCR surface expression (2). We are presently comparing microchip gene array data from BLIN-3 to that of other more typical MLL/AF4 cells in order to determine which B-lineage genetic pathways are targeted by the MLL/AF4 oncoprotein resulting in arrest of B-lineage development and apoptotic resistance to growth factor withdrawal.
