Acceleration of G(1) cooperates with core binding factor beta-smooth muscle myosin heavy chain to induce acute leukemia in mice.
The genes encoding the AML1 (RUNX1) or CBFbeta subunits of core binding factor (CBF) are commonly altered by translocation or mutation in human leukemias. Because CBF oncoproteins slow G(1), we sought to determine whether mutations that accelerate G(1) potentiate their ability to induce transformation. Wild-type or p16(INK4a)p19(ARF) (-/-) marrow cells transduced with CBFbeta-smooth muscle myosin heavy chain (SMMHC) were transplanted into wild-type, syngeneic recipients. CBFbeta-SMMHC significantly increased the development of acute leukemias from marrow lacking the overlapping p16p19 genes, based on analysis of Kaplan-Meier event-time distributions. Wild-type marrow was also transduced with vectors expressing either E7 alone or both E7 and CBFbeta-SMMHC. Combining oncogenes again increased leukemia formation. Exposing mice transplanted with CBFbeta-SMMHC-transduced cells to a mutagen, ethylnitrosourea, markedly accelerated leukemogenesis compared to expressing CBFbeta-SMMHC with loss of p16p19, indicating the need for multiple "hits" for transformation. The INV/p16p19 and INV/E7 leukemias were lymphoid and were clonal and retransplantable. Overall, these findings indicate that CBF mutations cooperate with genetic alterations that accelerate G(1) to induce acute leukemia.
Yang
Yandan
Y
Department of Oncology, Cancer Research Building, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA.
Wang
Weihua
W
Cleaves
Rebecca
R
Zahurak
Marianna
M
Cheng
Linzhao
L
Civin
Curt I
CI
Friedman
Alan D
AD
D000208:Acute Disease; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D007942:Leukemia, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018995:Myosin Heavy Chains / Q000235:genetics / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology; D050725:Papillomavirus E7 Proteins; D012190:Retroviridae / Q000235:genetics; D024745:Smooth Muscle Myosins / Q000235:genetics / Q000502:physiology*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; C059731:oncogene protein E7, Human papillomavirus type 16; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains