title: Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice.
abstract: The role of hyperactive RAS signaling is well established in myeloid malignancies but less clear in T-cell malignancies. The Kras2(LSL)Mx1-Cre (KM) mouse model expresses endogenous KRAS(G12D) in hematopoietic cells and is widely used to study mechanisms and treatment of myeloproliferative neoplasms (MPN). The model displays an intriguing shift from MPN to acute T-cell leukemia (T-ALL) after transplantation to wild-type mice, but the mechanisms underlying this lineage shift is unknown. Here, we show that KRAS(G12D) increases proliferation of both myeloid and T-cell progenitors, but whereas myeloid cells differentiate, T-cell differentiation is inhibited at early stages. Secondary mutations in the expanded pool of T-cell progenitors accompany T-ALL development, and our results indicate that the shift from myeloid to T-lymphoid malignancy after transplantation is explained by the increased likelihood for secondary mutations when the tumor lifespan is increased. We demonstrate that tumor lifespan increases after transplantation because primary KM mice die rapidly, not from MPN, but from KRAS(G12D) expression in nonhematopoietic cells, which causes intestinal bleeding and severe anemia. We also identify loss of the wild-type KRAS allele as a secondary mutation in all T-ALL cells and provide evidence that wild-type KRAS acts as a tumor suppressor in the T-cell lineage in mice.
authors.affiliation: 1] Department of Clinical Chemistry and Transfusion medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden [2] Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Staffas
authors.affiliation: Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Karlsson
authors.affiliation: Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Persson
authors.affiliation: Department of Clinical Chemistry and Transfusion medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Palmqvist
authors.affiliation: Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000483:Alleles; D000740:Anemia / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D017690:Cell Transplantation; D003001:Cloning, Molecular; D005434:Flow Cytometry; D011905:Genes, ras; D005838:Genotype; D006454:Hemoglobins / Q000737:chemistry; D051740:Ikaros Transcription Factor / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D006454:Hemoglobins; C000599897:KRAS4B protein, mouse; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)