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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

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

Published Date

  • July 14, 2011

Published In

Volume / Issue

  • 118 / 2

Start / End Page

  • 368 - 379

PubMed ID

  • 21586752

Pubmed Central ID

  • PMC3138689

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2010-12-326058

Language

  • eng

Conference Location

  • United States