Single Cell Analysis of Leukemia Initiation
Leukemias comprise approximately 30% of childhood cancers, and constitute a heterogeneous group of diseases defined by their diverse molecular abnormalities, which dictate disease pathogenesis, treatment response and clinical prognosis. Chromosomal rearrangements involving the MLL gene occur in both primary and treatment-related leukemias, and are associated with a poor prognosis. Animal models have improved our understanding of the role of MLL oncogenes in leukemia pathogenesis, but little is known about the primary alterations induced by MLL oncogene activation in human cells. Furthermore, previous studies have analyzed the average features displayed by populations of cells, which may vary in their individual reactions depending on their stage of differentiation and other intrinsic properties.
This proposal will characterize individual cells for their responses to molecular events that initiate acute leukemia. It is based on recent studies of ours using genome engineering to create endogenous activated MLL oncogenes with high efficiency in primary human cord blood stem and progenitor cells. Building on these advances, we propose to interrogate the sequential transcriptional changes that occur following endogenous MLL oncogene activation using single cell RNA-seq techniques. A whole transcriptome approach will define the sequential gene expression changes following activation of an endogenous cellular oncogene to define the transition from normal progenitor cells of origin to initiated cells representing the first steps in development of human acute leukemia. These studies hold the promise of identifying cell-of-origin specific transformation-associated events that may serve as novel targets for more selective and less toxic treatments with fewer long-term negative effects.