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MOUSE NF1 LEUKEMIA MODEL

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

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MOUSE NF1 LEUKEMIA MODEL

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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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