title: Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner.
abstract: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Zeyang
authors.initials: Z
authors.lastname: Li
authors.forename: Zhongde
authors.initials: Z
authors.lastname: Wang
authors.forename: Li Xuan
authors.initials: LX
authors.lastname: Tan
authors.forename: Myung-Jeom
authors.initials: MJ
authors.lastname: Ryu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meline
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.forename: Erik
authors.initials: E
authors.lastname: Ranheim
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D016026:Bone Marrow Transplantation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000502:physiology*; D011905:Genes, ras / Q000235:genetics* / Q000502:physiology; D018698:Glutamic Acid / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000628:therapy; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity / Q000235:genetics
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid