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.
