scid Thymocytes with TCRbeta gene rearrangements are targets for the oncogenic effect of SCL and LMO1 transgenes.
SCL and LMO1 were both discovered by virtue of their activation by chromosomaltranslocation in patients with T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of SCL and LMO1 in the thymus of transgenic mice leads to T-ALL at a young age. scid (severe combined immunodeficient) mice are unable to efficiently recombine antigen receptor genes and consequently display a developmental block at the CD4-CD8- to CD4+CD8+ transition. To test the hypothesis that this developmental block would protect SCL/LMO1 transgenic mice from developing T-ALL, we crossed the SCL and LMO1 transgenes onto a scid background. The age of onset for T-ALL in the SCL/LMO1/scid mice was significantly delayed (P < 0.001) compared with SCL/LMO1/wild-type mice. Intriguingly, all of the SCL/LMO1/scid malignancies displayed clonal, in-frame TCRbeta gene rearrangements. Taken together, these findings suggest that the "leaky" scid thymocyte that undergoes a productive TCRbeta gene rearrangement is susceptible to the oncogenic action of SCL and LMO1 and additionally suggests that TCRbeta gene rearrangements may be required for the oncogenic action of SCL and LMO1.
Chervinsky
D S
DS
Genetics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Lam
D H
DH
Melman
M P
MP
Gross
K W
KW
Aplan
P D
PD
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002999:Clone Cells; D003433:Crosses, Genetic; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000276:immunology*; D060588:LIM Domain Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology; D008297:Male; D008667:Metalloproteins / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology; D011518:Proto-Oncogene Proteins; D011519:Proto-Oncogenes / Q000235:genetics; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000502:physiology; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C513044:Lmo1 protein, mouse; C489366:Tal1 protein, mouse