Normal Hematopoiesis and Neurofibromin -Deficient Myeloproliferative Disease Require Erk

Abstract 704 Neurofibromatosis type 1 predisposes individuals to the development of juvenile myelomonocytic leukemia, a fatal myeloproliferative disease (MPD). In genetically engineered murine models, nullizygosity of Nf1, a tumor suppressor gene which 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 plethoric mitogenic roles in diverse cell types. However, genetic studies examining Erk1/29s 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 does not grossly compromise myelopoiesis, dual Erk1/2 ablation rapidly ablates granulocyte and monocyte production, diminishes progenitor cell number, and prevents HSPC proliferation. Intriguingly, genetic disruption of Erk1/2 in the context of Nf1 nullizygosity ( Mx1Cre + Nf1 flox/flox Erk1 −/− Erk2 flox/flox ) fully protects against the genesis of MPD. Collectively, we identify 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 for the attenuation of a leukemia that is otherwise resistant to traditional therapy. Disclosures: No relevant conflicts of interest to declare.