Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice
Tiffany Chang, … , Benjamin S. Braun, Kevin Shannon
Tiffany Chang, … , Benjamin S. Braun, Kevin Shannon
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):335-339. https://doi.org/10.1172/JCI63193.
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Brief Report

Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice

Abstract

Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that is refractory to conventional chemotherapy. Conditional inactivation of the Nf1 tumor suppressor in hematopoietic cells of mice causes a progressive MPN that accurately models JMML and chronic myelomonocytic leukemia (CMML). We characterized the effects of Nf1 loss on immature hematopoietic populations and investigated treatment with the MEK inhibitor PD0325901 (hereafter called 901). Somatic Nf1 inactivation resulted in a marked expansion of immature and lineage-committed myelo-erythroid progenitors and ineffective erythropoiesis. Treatment with 901 induced a durable drop in leukocyte counts, enhanced erythropoietic function, and markedly reduced spleen sizes in mice with MPN. MEK inhibition also restored a normal pattern of erythroid differentiation and greatly reduced extramedullary hematopoiesis. Remarkably, genetic analysis revealed the persistence of Nf1-deficient hematopoietic cells, indicating that MEK inhibition modulates the proliferation and differentiation of Nf1 mutant cells in vivo rather than eliminating them. These data provide a rationale for performing clinical trials of MEK inhibitors in patients with JMML and CMML.

Authors

Tiffany Chang, Kimberly Krisman, Emily Harding Theobald, Jin Xu, Jon Akutagawa, Jennifer O. Lauchle, Scott Kogan, Benjamin S. Braun, Kevin Shannon

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Figure 1

901 reduces myeloproliferation and enhances erythropoiesis in Mx1-Cre;Nf1flox/flox (Nf1) mice.

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901 reduces myeloproliferation and enhances erythropoiesis in Mx1-Cre;Nf...
Nf1 and WT mice were treated with vehicle (Veh) or 901 for 10 weeks. (A) wbc counts, (B) hemoglobin (HB) concentrations, (C) and percentage of reticulocytes in the blood of Nf1 mice given vehicle (blue) or 901 (orange) and of WT mice treated with vehicle (black) or 901 (gray). (D) Spleen weights at the end of the trial. Mean and SEM are shown (n = 11–13 per group). Asterisks indicate significant differences between Nf1 mice that received 901 and vehicle (*P < 0.05; **P < 0.001; ***P < 0.0001). (E) Kaplan-Meier analysis revealed a trend toward enhanced survival in 901-treated Nf1 mice (P = NS). (F) PCR amplification of BM DNA from individual WT and Nf1 mice at the end of the trial (n = 11–13 per group). Notably, both 901- and vehicle-treated Nf1 mutant mice demonstrated complete excision of exon 31.