Major strides have been made in the treatment pediatric B-lymphoblastic leukemia (B-ALL) in the past several decades. Yet, certain subtypes of B-ALL remain refractory to current regimens- including those that carry translocations of the MLL gene. To target novel pathways in these leukemias, we undertook a gene expression profiling study and analyzed the data with a view towards novel biological pathways that affect gene expression, particularly RNA binding proteins (RBPs). RBPs mediate a diverse set of cellular functions, but many have a significant function in gene expression regulation by regulating stability of mRNA and/or translation. Interestingly, we found that one of these RBPs, insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), is highly upregulated in B-lymphoblastic leukemia with translocations of the MLL gene, and that this protein is overexpressed in patient samples when compared with normal B-cell progenitors. IGF2BP3 is known to have a growth-promoting role in certain epithelial malignancies, but in vivo studies are lacking. Based on our preliminary findings, we hypothesize that IGF2BP3 is oncogenic in the hematopoietic system and that it is required for the survival of B-ALL cells. Here, we will test whether this protein is sufficient for oncogenesis in the hematopoietic system in vivo, whether it is required for the growth and survival of leukemic and normal B-cells, and to define its downstream targets. The completion of these aims will increase our understanding of RBPs in B-leukemogenesis, and point to a new therapeutic modality in treating B-ALL with MLL translocations.
B-acute lymphoblastic leukemia is a significant health problem in the United States and certain subtypes of this disease remain very difficult to treat. This proposal seeks to bring together remarkable progress in high- throughput molecular biological techniques with this important disease to solve problems in pathogenesis and designing future therapeutic approaches. Successful completion of this proposal will yield new approaches to leukemia diagnosis, classification and therapy, and will improve the lives of countless Americans who suffer from aggressive forms of B-cell malignancy.
