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NF1 Mouse Model Reveals Insights into Myeloproliferative Disorders and Myeloid Leukemias

The NF1 gene encodes a GTPase-activating protein for Ras, and mutations in NF1 predispose children to myeloproliferative disorders (MPD) and myeloid leukemias. Studies show that both murine and human leukemias exhibit loss of the normal Nf1/NF1 allele, leading to hyperactive Ras signaling. Nf1-deficient fetal hematopoietic cells can induce MPD in irradiated hosts, highlighting the importance of understanding Ras signaling mechanisms. Additionally, retroviral infections in fetal liver cells create growth factor-dependent cell pools that uniformly express myeloid markers, crucial for studying hematopoiesis.

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NF1 Mouse Model Reveals Insights into Myeloproliferative Disorders and Myeloid Leukemias

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  1. MOUSE NF1 LEUKEMIA MODEL • NF1 encodes a GTPase activating protein for Ras • Children with NF1 and heterozygous Nf1 mutant mice are predisposed to myeloproliferative disorders (MPD) and myeloid leukemias • Murine and human leukemias show loss of normal Nf1/NF1 allele, and hyperactive Ras signaling • Nf1-deficient fetal hematopoietic cells consistently induce MPD in irradiated hosts • Marrow cells can be used to interrogate Ras signaling

  2. Processing Ras GDP Growth Factor Ras GDP P i GTP Neurofibromin p120 GAP SOS, GRF, GRP GDP Ras GTP NF1 or RAS Mutation ? Raf PI3’-Kinase Ral GDS MEK ? Cell Survival ERK

  3. MSCV-Myb LINES • fetal liver cells infected with a retrovirus that encodes a truncated Myb virus (Gonda et al., EMBO J 8,1777, 1989) and EGFP in the MSCV backbone (Hawley et al., Gene Ther 1, 136, 1994) • generates pools of cells after ~2 weeks that remain growth factor-dependent and uniformly express myeloid markers (Gr1/Mac-1) • 5-10% of cultures form CFU-GM in methylcellulose

  4. GM-CSF(ng/ml) - + ++ - - - + ++ - - IL-3(ng/ml) - - - + ++ - - - + ++ P-ERK1 P-ERK2 Wehi + control Nf1 -/- WT MAP KINASE ACTIVATION IN Nf1-/- MSCV-Myb CELLS ERK1 ERK2

  5. DEFECTIVE APOPTOSIS OFNf1 -/- Myb CELLS + GM-CSF - GM-CSF

  6. INHIBITING PI-3 KINASE INDUCES APOPTOSIS IN Nf1 -/- Myb CELLS DMSO PD 184352 LY294002 Annexin V staining

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