title: Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation.
abstract: KRAS is often mutated in human hematopoietic malignancies, including juvenile myelomonocytic leukemia (JMML) and T-cell lymphoblastic leukemia/lymphoma (TLL/L). However, the exact role and function of oncogenic KRAS mutations in the initiation and progression of JMML and TLL/L remain elusive. Here, we report the use of a mouse bone marrow transplantation model to study oncogenic Kras-induced leukemogenesis. We show that as the first genetic hit, oncogenic Kras mutations initiate both JMML and TLL/L, but with different efficiencies. Limiting dilution analyses indicated that an oncogenic Kras mutation alone is insufficient to produce frank malignancy. Instead, it cooperates with additional subsequent genetic event(s). Moreover, transplantation of highly purified hematopoietic stem cells (HSCs) and myeloid progenitors identified HSCs as the primary target for the oncogenic Kras mutation. Karyotypic analysis further indicated that secondary genetic hit(s) target lineage-specific progenitors rather than HSCs for terminal tumor transformation into leukemic stem cells. Thus, we propose the cellular mechanism underlying oncogenic Kras-induced leukemogenesis, with HSCs as the primary target by the oncogenic Kras mutations and lineage-committed progenitors as the final target for cancer stem cell transformation. Our model might be also applicable to other solid tumors harboring oncogenic Kras mutations.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA. zhang@oncology.wisc.edu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Harwin
authors.initials: H
authors.lastname: Sidik
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D002871:Chromosome Banding; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D007942:Leukemia, Experimental / Q000235:genetics / Q000473:pathology*; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*
chemical_list: C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)