title: NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfβ-SMMHC via activation of MEK/ERK axis.
abstract: Acute myeloid leukemia (AML) results from the activity of driver mutations that deregulate proliferation and survival of hematopoietic stem cells (HSCs). The fusion protein CBFβ-SMMHC impairs differentiation in hematopoietic stem and progenitor cells and induces AML in cooperation with other mutations. However, the combined function of CBFβ-SMMHC and cooperating mutations in preleukemic expansion is not known. Here, we used Nras(LSL-G12D); Cbfb(56M) knock-in mice to show that allelic expression of oncogenic Nras(G12D) and Cbfβ-SMMHC increases survival of preleukemic short-term HSCs and myeloid progenitor cells and maintains the differentiation block induced by the fusion protein. Nras(G12D) and Cbfβ-SMMHC synergize to induce leukemia in mice in a cell-autonomous manner, with a shorter median latency and higher leukemia-initiating cell activity than that of mice expressing Cbfβ-SMMHC. Furthermore, Nras(LSL-G12D); Cbfb(56M) leukemic cells were sensitive to pharmacologic inhibition of the MEK/ERK signaling pathway, increasing apoptosis and Bim protein levels. These studies demonstrate that Cbfβ-SMMHC and Nras(G12D) promote the survival of preleukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define Nras(LSL-G12D); Cbfb(56M) mice as a valuable genetic model for the study of inversion(16) AML-targeted therapies.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester MA; and.
authors.forename: Liting
authors.initials: L
authors.lastname: Xue
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester MA; and.
authors.forename: John A
authors.initials: JA
authors.lastname: Pulikkan
authors.affiliation: Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester MA; and.
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Castilla
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D055879:Gene Knock-In Techniques; D007942:Leukemia, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011289:Preleukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C095514:CBFbeta-MYH11 fusion protein; D008565:Membrane Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse