Origin and significance of altered replication timing in pediatric leukemia

B-lineage acute lymphocytic leukemia (B-ALL) is the most common childhood malignancy, yet we still do not understand the molecular mechanisms that lead to the genesis of this disease and there are no known strategies for its prevention. Pediatric B-ALL cells deviate from non-leukemic human B cells in the temporal order in which segments of their chromosomal DNA are duplicated (replication timing. The laboratory of FSU Professor of Biological Science Dave Gilbert, in collaboration with the Children’s Oncology Group and the FSU CGPM, is generating genome-wide replication timing profiles from a large cohort of pediatric B-ALL patients lacking prognostic markers and to potentially identify new biomarkers for pediatric leukemia. In addition, we are profiling the changes in replication timing that accompany the process by which normal human B-cells are generated to determine which replication timing alterations in leukemia derive from the cell type of origin. Finally, we are developing a novel model of leukemic transformation of normal human hematopoietic cells to assess when and in what cell types evidence of “aberrant replication timing” first appears during the process of leukemogenesis. Replication timing has the potential to provide a new genre of biomarkers for diagnosis. In addition, replication timing reports on an undeveloped aspect of chromosome biology that is altered in B-ALL. Hence, studies of the cellular origin and mechanistic determinants of these replication timing alterations will provide novel insights into the underlying mechanisms of B-ALL.