Evolutionary trajectories and cell-of-origin of TCF3-ZNF384&PTPN11 mutations in monozygotic twins with concordant B-ALL

Rearrangements of the MLL gene are associated with aggressive acute leukemia. The most common MLL-rearrangement is MLL-AF4 which is the hallmark genetic abnormality of infant t(4;11) pro-B ALL, it also has one of the lowest mutation rates among cancers. It is associated with poor prognosis and displays a very brief latency, raising the question of how this disease evolves so rapidly. Despite worldwide efforts, progress about its aetiology, pathogenesis and cellular origin remains unresolved. In order to contribute to these unresolved questions, we have applied a CRISPR/Cas9-mediated genome editing strategy to recreate the t(4;11) translocation in HSPC isolated from different ontogeny stages including fetal liver and cord blood derived HSPCs. The genome edited HSPCs at distinct developmental stages have been functionally assayed to address whether t(4;11) initiates leukemogenesis on its own or whether secondary cooperating hits are required for an overt leukemia. These pioneering studies will reveal a precise understanding on the impact of such chromosomal rearrangements on leukemogenesis, and provide a humanized disease model, offering a platform for new treatment strategies.