Role of MEK1 signaling in the regulation of hematopoiesis and leukemogenesis

The Raf/MEK/ERK pathway has long been implicated in leukemogenesis. Mostly, the proteins within the pathway are considered pro-oncogenic, and MEK inhibitors block K-RasG12D-driven myelomonocytic leukemia in preclinical mouse models. Intriguingly, however, silencing of the MEK1 gene has been reported to accelerate Myc- driven lymphomagenesis. We and others have shown that disruption of the mek1 gene results in a recessive lethal phenotype, with the mutant embryos dying at around 9.5 days of gestation due to abnormal placenta development. Embryonic lethality can be circumvented by epiblast-restricted deletion, which yields viable, fertile mek1 deficient mice. Using these mice, we have recently reported that MEK1 is essential for the regulation of the timing and strength of ERK signaling. By phosphorylating the T292 site in the proline-rich region of MEK1, ERK exerts negative feedback control on MEK1/MEK2 dimers. If MEK1 is absent, this control is disabled, leading to increased ERK signaling. More recently, we have discovered that the same ERK-dependent phosphosite of MEK1 is essential for proper membrane localization of the phosphatase and tensin homologue deleted on chromosome ten (PTEN), which functions as a tumor suppressor in leukemogenesis. PTEN converts PIP3 to PIP2, thereby inhibitingerminating AKT activation; therefore, both MEK1 ablation and MEK inhibition lead to AKT activation. In vivo, MEK1 ablation causes a complex immunopathology comprising inflammation, lupus-like autoimmune disease, and myeloproliferation, partially phenocopying PTEN heterozygous mice. We have not, however, found any evidence of leukemias or lymphoma in these animals. Based on this, we now intend to systematically investigate the role of MEK1 in myeloproliferation and leukemogenesis and the molecular mechanisms underlying it. Tissue-restricted MEK1 ablation and bone marrow transplantation will be employed to distinguish between cell-autonomous and non-cell autonomous effects of MEK1 ablation; mouse models of acute myeloid leukemia will be used to test whether MEK1 suppresses leukemogenesis by one or more of the oncogenes implicated in this disease. MEK1 deletion at different stages will elucidate whether MEK1 exerts its function during the establishment or maintenance of the disease. Finally, both candidate and unbiased approaches will be used to elucidate the molecular basis of MEK1`s function. The basic mechanistic information yielded by the proposed research will advance the understanding of the cross-talk between the MEK/ERK and PI3K pathway, provide a mechanistic basis for the observed upregulation of the AKT pathway in leukemic cells treated with MEK inhibitors, and therefore be useful for the design of novel therapies.