Initiation of MLL-rearranged AML is orchestrated by C/EBPa
Acute Myeloid Leukemia (AML) is associated with a number of genetic and epigenetic events that result in malignant transformation of hematopoietic cells. In particular, transcription factors essential for normal hematopoiesis and stem cell function are often found mutated leading to the formation of leukemic stem cells and the accumulation of immature blasts. Among them, translocations involving the mixed lineage leukemia (MLL) gene at chromosome band 11q23 are one of the most commonly events (~10 %) and is associated with poor prognosis in human leukemias. Whereas the downstream effects of MLL-fusion proteins are well established, the modes on which these effects are mediated are still unclear and whether MLL-fusion proteins are dependent on other transcriptional regulators or act alone remains elusive. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBPa to be up-regulated in the AML samples, suggesting that C/EBPa might collaborate with MLL-fusion proteins in the initial transformation process. We could show that transformation by MLL-fusion proteins is dependent on C/EBPa activity both in early progenitors as well as in GMPs. In contrast, C/EBPa was found to be indispensable in an already established leukemia. These finding led us to study the early transcriptional changes induced by MLL-ENL expression and we identified a combined C/EBPa / MLL-ENL transcriptional signature. Collectivly, our data shows that C/EBPa configure a proper chromatin state required for MLL-fusions to induce malignant transformation. Overall design: Histone modification profiles (H3K4me3 and H3K27me3) in haematopoietic progenitor cells (preGM, wild type and Cebpa knock out), and C/EBPa binding in GMP cells