Dissecting lineage plasticity in mixed phenotype acute leukemias
Mentor Name: Elvin Wagenblast
Mixed phenotype acute leukemia (MPAL) is a particularly challenging disease that uniquely displays characteristics of both primary types of acute leukemia. Given its aggressive nature and propensity to switch between lymphoid and myeloid types, MPAL has been associated with poor clinical outcomes in children. Rearrangements of the gene ZNF384 are present in about 50% of MPAL cases, and lineage plasticity is frequently seen after chemo- or immunotherapy. There is a major gap in understanding the origin and evolution of MPAL due to a lack of suitable experimental models. Utilizing cutting-edge genome engineering technology, this project will generate a model where either a TCF3-ZNF384 fusion protein or EP300-ZNF384 fusion protein is replicated within human primary blood stem cells. Then, we will introduce chromosomal translocations at the TCF3/ZNF384 or EP300/ZNF384 natural break sites to generate endogenous expression of the TCF3-ZNF384 or EP300-ZNF384 fusion. We will assess if these innovative models recapitulate MPAL initiation, which would then allow a granular examination of the genetic and molecular behavior of these cells, especially in conjunction with standard chemotherapy and immunotherapy.
