Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk
Karl Staser, … , Feng-Chun Yang, D. Wade Clapp
Karl Staser, … , Feng-Chun Yang, D. Wade Clapp
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):329-334. https://doi.org/10.1172/JCI66167.
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Brief Report

Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk

Abstract

Neurofibromatosis type 1 (NF1) predisposes individuals to the development of juvenile myelomonocytic leukemia (JMML), a fatal myeloproliferative disease (MPD). In genetically engineered murine models, nullizygosity of Nf1, a tumor suppressor gene that encodes a Ras-GTPase–activating protein, results in hyperactivity of Raf/Mek/Erk in hematopoietic stem and progenitor cells (HSPCs). Activated Erk1/2 phosphorylate kinases and transcription factors with myriad mitogenic roles in diverse cell types. However, genetic studies examining Erk1/2’s differential and/or combined control of normal and Nf1-deficient myelopoiesis are lacking. Moreover, prior studies relying on chemical Mek/Erk inhibitors have reached conflicting conclusions in normal and Nf1-deficient mice. Here, we show that while single Erk1 or Erk2 disruption did not grossly compromise myelopoiesis, dual Erk1/2 disruption rapidly ablated granulocyte and monocyte production in vivo, diminished progenitor cell number, and prevented HSPC proliferation in vitro. Genetic disruption of Erk1/2 in the context of Nf1 nullizygosity (Mx1Cre+Nf1flox/floxErk1–/–Erk2flox/flox) fully protects against the development of MPD. Collectively, we identified a fundamental requirement for Erk1/2 signaling in normal and Nf1-deficient hematopoiesis, elucidating a critical hematopoietic function for Erk1/2 while genetically validating highly selective Mek/Erk inhibitors in a leukemia that is otherwise resistant to traditional therapy.

Authors

Karl Staser, Su-Jung Park, Steven D. Rhodes, Yi Zeng, Yong Zheng He, Matthew A. Shew, Jeffrey R. Gehlhausen, Donna Cerabona, Keshav Menon, Shi Chen, Zejin Sun, Jin Yuan, David A. Ingram, Grzegorz Nalepa, Feng-Chun Yang, D. Wade Clapp

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Figure 3

Nf1-deficient MPD requires Erk.

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Nf1-deficient MPD requires Erk. (A) CD45.2+ bone marrow cells harvest...
(A) CD45.2+ bone marrow cells harvested from Mx1Cre+Nf1flox/floxErk1–/–Erk2flox/flox mice were mixed with CD45.1+ WT bone marrow cells and transplanted into lethally irradiated CD45.1/2+ recipients, alongside control groups, as shown. After 4 months, all mice received poly(I:C) and were then killed approximately 6 months later. (B and C) Erk1, Erk2, and Nf1 disruption in the hematopoietic system protects against the phenotype observed in Nf1-KO recipients, which have enlarged spleens with effacement of the regular white pulp cellular architecture. *P < 0.05; **P < 0.01; ***P < 0.001, all vs. Nf1-KO; all other comparisons P > 0.05, 1-way ANOVA with Bonferroni’s correction. Original magnification, ×100 (top panels); ×300 (bottom panels). (D) Similarly, the Nf1-Erk1/2-KO recipients show ablated CD45.2+ populations in the peripheral blood, similar to the Erk1/2-KO cohort. **P < 0.01; ***P < 0.001, all vs. Nf1-KO, 1-way ANOVA with Dunnett’s correction. In comparison, the Nf1-KO recipients show expansion of total CD45.2+ cells, total CD45.2+ myeloid cells, and total CD45.2+ granulocytes in the peripheral blood. (E) In the bone marrow, the Nf1-Erk1/2-KO recipients show few CD45.2+ myeloid cells, including both CD45.2+CD3–B220–Gr1+Mac1+ and CD45.2+CD3–B220–Gr1–Mac+ populations, which contrasts with the increased frequency observed in the Nf1-KO cohort. *P < 0.05; **P < 0.01; ***P < 0.001, all vs. Nf1-KO, 1-way ANOVA with Dunnett’s correction.