The dual-specificity kinases MEK1 and MEK2 act downstream of RAS/RAF to induce ERK activation, which is generally considered protumorigenic. Activating MEK mutations have not been discovered in leukemia, in which pathway activation is caused by mutations in upstream components such as RAS or Flt3. The anti-leukemic potential of MEK inhibitors is being tested in clinical trials; however, downregulation of MEK1 promotes Eμ-Myc-driven lymphomagenesis and MEK1 ablation induces myeloproliferative disease in mice, raising the concern that MEK inhibitors may be inefficient or counterproductive in this context. We investigated the role of MEK1 in the proliferation of human leukemic cell lines and in retroviral models of leukemia. Our data show that MEK1 suppression via RNA interference and genomic engineering does not affect the proliferation of human leukemic cell lines in culture; similarly, MEK1 ablation does not impact the development of MYC-driven leukemia in vivo. In contrast, MEK1 ablation significantly reduces tumorigenesis driven by Nras alone or in combination with Myc. Thus, while MEK1 restricts proliferation and tumorigenesis in some cellular and genetic contexts, it cannot be considered a tumor suppressor in the context of leukemogenesis. On the contrary, its role in NRAS-driven leukemogenesis advocates the use of MEK inhibitors, particularly in combination with PI3K/AKT inhibitors, in hematopoietic malignancies involving RAS activation.
Keywords: MEK1; MYC; NRAS; leukemia.