c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations.
Ectopic expression of c-Myc (Myc) in most primary cell types results in programmed cell death, and malignant transformation cannot occur without additional mutations that block apoptosis. The development of Myc-induced lymphoid tumors has been well studied and supports this model. Myc can be upregulated in acute myeloid leukemia (AML), but its exact role in myeloid leukemogenesis is unclear. To study its role in AML, we used a murine stem cell virus (MSCV) retroviral gene transfer/transplantation system to broadly express Myc in the bone marrow of mice either alone or in combination with antiapoptotic mutations. Myc expression in the context either of Arf/Ink4a loss or Bcl-2 coexpression induced a mixture of acute myeloid and acute lymphoid leukemias (AML+ALL). In the absence of antiapoptotic mutations however, all mice transplanted with MSCV-Myc (100%, n = 110) developed AML exclusively. MSCV-Myc-induced AML was polyclonal, readily transplantable, possessed an intact Arf-p53 pathway, and did not display cytogenetic abnormalities by spectral karyotyping (SKY) analysis. Lastly, we found that Myc preferentially stimulated the growth of myeloid progenitor cells in methylcellulose. These data provide the first direct evidence that Myc is a critical downstream effector of myeloid leukemogenesis and suggest that myeloid progenitors are intrinsically resistant to Myc-induced apoptosis.
Department of Medicine and Genetics, Division of Oncology, Saint Louis, MO 63110, USA.
Hui
H
Luo
Qing
Q
Li
Julie
J
O'Neal
Friederike
F
Kreisel
Michelle M
MM
Le Beau
Michael H
MH
Tomasson
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002460:Cell Line; D017690:Cell Transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D008747:Methylcellulose / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D017422:Sequence Analysis, DNA; D013997:Time Factors; D015854:Up-Regulation
D019941:Cyclin-Dependent Kinase Inhibitor p16; C489428:Myc protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D049452:Green Fluorescent Proteins; D008747:Methylcellulose; D004247:DNA