Submitted January 18, 2008
Accepted November 27, 2008
Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation
Jing Zhang*, Jing Wang, Yangang Liu, Harwin Sidik, Ken H Young, Harvey F Lodish, and Mark D Fleming
Whitehead Institute for Biomedical Research, Cambridge, MA, United States
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States
Department of Molecular Biology, University of Wisconsin-Madison, Madison, WI, United States
Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
Department of Pathology, Children's Hospital Boston, Boston, MA, United States
* Corresponding author; email: zhang{at}oncology.wisc.edu.
K-ras 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 K-ras 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 K-ras mutations initiate both JMML and TLL/L, but with different efficiencies. Limiting dilution analyses indicated that an oncogenic K-ras mutation alone is insufficient to produce frank malignancy. Rather, it co-operates 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 K-ras 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 being the primary target by the oncogenic K-ras mutations and lineage-committed progenitors being the final target for cancer stem cell transformation. Our model might be also applicable to other solid tumors harboring oncogenic K-ras mutations.
