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

Blood | Jul 14, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21586752

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 RIS Download

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

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Associated grants

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

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