Only hematopoietic stem and progenitor cells from cord blood are susceptible to malignant transformation by MLL-AF4 translocations

MLL rearrangements (MLLr) play a crucial role in leukemogenesis. Dependent on age, major differences exist regarding disease frequency, main fusion partners and prognosis. In infants, up to 80% of acute lymphoid leukemia (ALL) bear t(4;11) resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear t(9;11) with an intermediate prognosis. The reasons for these differences are only poorly understood. Recently, we established an efficient human patient-specific CRISPR/Cas9-based MLLr model in hematopoietic stem and progenitor cells (HSPCs) derived from human cord blood (huCB) faithfully mimicking the underlying biology of the disease. Here, we transfer this model into an adult system using HSPCs from adult bone marrow (huBM) allowing us to investigate the impact of the cell of origin and fusion partner on disease development. RNA-Seq uncovered an absent downregulation of FFAR2 in t(4;11) huBM, an epigenetic tumor suppressor, potentially responsible for the inability of MLL-AF4 to immortalize adult cells under myeloid conditions.