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Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner.

Both monoallelic and biallelic oncogenic NRAS mutations are identified in human leukemias, suggesting a dose-dependent role of oncogenic NRAS in leukemogenesis. Here, we use a hypomorphic oncogenic Nras allele and a normal oncogenic Nras allele (Nras G12D(hypo) and Nras G12D, respectively) to create a gene dose gradient ranging from 25% to 200% of endogenous Nras G12D/+. Mice expressing Nras G12D(hypo)/G12D(hypo) develop normally and are tumor-free, whereas early embryonic expression of Nras G12D/+ is lethal. Somatic expression of Nras G12D/G12D but not Nras G12D/+ leads to hyperactivation of ERK, excessive proliferation of myeloid progenitors, and consequently an acute myeloproliferative disease. Using a bone marrow transplant model, we previously showed that ∼ 95% of animals receiving Nras G12D/+ bone marrow cells develop chronic myelomonocytic leukemia (CMML), while ∼ 8% of recipients develop acute T-cell lymphoblastic leukemia/lymphoma [TALL] (TALL-het). Here we demonstrate that 100% of recipients transplanted with Nras G12D/G12D bone marrow cells develop TALL (TALL-homo). Although both TALL-het and -homo tumors acquire Notch1 mutations and are sensitive to a γ-secretase inhibitor, endogenous Nras G12D/+ signaling promotes TALL through distinct genetic mechanism(s) from Nras G12D/G12D. Our data indicate that the tumor transformation potential of endogenous oncogenic Nras is both dose- and cell type-dependent.

Pubmed ID: 21586752


  • Wang J
  • Liu Y
  • Li Z
  • Wang Z
  • Tan LX
  • Ryu MJ
  • Meline B
  • Du J
  • Young KH
  • Ranheim E
  • Chang Q
  • Zhang J



Publication Data

July 14, 2011

Associated Grants

  • Agency: NCRR NIH HHS, Id: 1UL1RR025011
  • Agency: NICHD NIH HHS, Id: P30 HD003352

Mesh Terms

  • Amino Acid Substitution
  • Animals
  • Aspartic Acid
  • Bone Marrow Transplantation
  • Cell Transformation, Neoplastic
  • Female
  • Gene Dosage
  • Genes, ras
  • Glutamic Acid
  • Hematologic Neoplasms
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Oncogenes
  • Organ Specificity