Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk

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

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)329-334
Number of pages6
JournalJournal of Clinical Investigation
Volume123
Issue number1
DOIs
StatePublished - Jan 2 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Staser, K., Park, S. J., Rhodes, S. D., Zeng, Y., He, Y. Z., Shew, M. A., Gehlhausen, J. R., Cerabona, D., Menon, K., Chen, S., Sun, Z., Yuan, J., Ingram, D. A., Nalepa, G., Yang, F. C., & Clapp, D. W. (2013). Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. Journal of Clinical Investigation, 123(1), 329-334. https://doi.org/10.1172/JCI66167