Research ArticleCancer

A MEK Inhibitor Abrogates Myeloproliferative Disease in Kras Mutant Mice

Science Translational Medicine  30 Mar 2011:
Vol. 3, Issue 76, pp. 76ra27
DOI: 10.1126/scitranslmed.3001069

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A MEKanistic Strategy for Beating Leukemia

Overactivity of the Ras master signaling molecule has been implicated in both juvenile and chronic myelomonocytic leukemias (JMML and CMML). Despite its involvement in these leukemias, it has proven difficult to block either oncogenic Ras or its downstream signaling components. To address this issue, Lyubynska et al. used a mouse model with a mutation in the Kras gene (KrasG12D) that recapitulates features of the human myeloproliferative neoplasms JMML and CMML. They crossed two existing engineered strains to obtain the Mx1-Cre, KrasG12D mouse, which rapidly develops a progressive myeloproliferative neoplasm that is characterized by an increase in white blood cells (leukocytosis), an enlargement of the spleen (splenomegaly), and a lowered red blood cell count (anemia). Primary hematopoietic progenitor cells from the bone marrow of these mice display an overactive Raf/mitogen-activated or extracellular signal–regulated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) signaling pathway, which might be deregulated by oncogenic Ras; the authors therefore wondered whether blocking the downstream components of this pathway would be sufficient to block the effects of mutant Ras. So, they treated their 8-week-old Mx1-Cre, KrasG12D mice (with well-established myeloproliferative neoplasms) with PD0325901, a potent inhibitor of MEK, which is a signaling molecule that operates downstream of Ras. Compared to untreated mice, mice that received the MEK inhibitor demonstrated reduced leukocyte counts, disappearance of anemia, reduced spleen size, and prolonged survival—all of which indicate that PD0325901 reduces the severity of myeloproliferative disease. Lyubynska et al. attributed this positive effect to the ability of the MEK inhibitor to modulate the differentiation of bone marrow hematopoietic progenitor cells carrying the KrasG12D mutation, rather than boosting the proliferation of normal bone marrow progenitor cells.

Although the effect of the Kras mutation might not be completely eliminated by MEK inhibition, the value of this new therapeutic strategy lies in reducing the symptoms caused by myeloproliferative neoplasms. Conventional chemotherapy exerts a purely antiproliferative effect on the rogue mutant hematopoietic progenitor cells, but PD0325901, in addition to restoring normal proliferation and differentiation programs for mutant myeloid progenitor cells, also helped to “rebalance” the hematopoietic system in vivo, despite continued KrasG12D expression. This intriguing study suggests that MEK inhibitors might be of clinical benefit for treating patients with JMML and CMML.