Retroviral expression of leukemogenic oncogenes in the murine hematopoietic system is essential but not sufficient to induce acute
leukemia. Proviral integration-mediated elevated expression of the
meningioma 1 (MN1) oncogene suggested MN1 acting as cooperating event in mixed-lineage
leukemia 1 (MLL) and eleven nineteen
leukemia (ENL)-induced murine
leukemia. Indeed, co-expression of MN1 with MLL-ENL enhanced transformation in vivo, and resulted in a significantly reduced latency for induction of an aggressive acute
leukemia when compared with MN1 or MLL-ENL alone. In addition, co-expression of MN1 increased the granulocyte macrophage progenitor cell population with
leukemia-initiating properties as shown in secondary
transplantation experiments. Gene expression profiling experiments identified putative downstream MN1 targets, of which
FMS-like tyrosine kinase 3 (FLT3) and CD34 were upregulated in both MN1-overexpressing murine
leukemias and in pediatric acute
leukemias with high MN1 levels. Interestingly,
small interfering RNA (
siRNA)-mediated MN1 knockdown resulted in cell cycle arrest and impaired clonogenic growth of human
leukemia cell lines with high MN1 levels. Our work shows for the first time that high MN1 levels are important for the growth of leukemic cells, and that increased MN1 expression can synergize with MLL-ENL and probably other transforming fusion genes in
leukemia induction through a distinct gene expression program that is able to expand the
leukemia-initiating cell population.