Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice.
The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms of proliferation, apoptosis, clonality, and immunophenotype prior to the onset of a frank malignancy. At 4 weeks of age, thymocytes from SCL LMO1 mice show 70% fewer total thymocytes, with increased rates of both proliferation and apoptosis, than control thymocytes. At this age, a clonal population of thymocytes begins to populate the thymus, as evidenced by oligoclonal T-cell-receptor gene rearrangements. Also, there is a dramatic increase in immature CD44(+) CD25(-) cells, a decrease in the more mature CD4(+) CD8(+) cells, and development of an abnormal CD44(+) CD8(+) population. An identical pattern of premalignant changes is seen with either a full-length SCL protein or an amino-terminal truncated protein which lacks the SCL transactivation domain, demonstrating that the amino-terminal portion of SCL is not important for leukemogenesis. Lastly, we show that the T-ALL which develop in the SCL LMO1 mice are strikingly similar to those which develop in E2A null mice, supporting the hypothesis that SCL exerts its oncogenic action through a functional inactivation of E proteins.
Chervinsky
D S
DS
Departments of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Zhao
X F
XF
Lam
D H
DH
Ellsworth
M
M
Gross
K W
KW
Aplan
P D
PD
D016475:3T3 Cells; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015329:Gene Rearrangement, T-Lymphocyte; D018257:Helix-Loop-Helix Motifs / Q000235:genetics / Q000502:physiology*; D060588:LIM Domain Proteins; D015458:Leukemia, T-Cell / Q000209:etiology*; D008667:Metalloproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000002:abnormalities / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; C513044:Lmo1 protein, mouse; C489366:Tal1 protein, mouse; C075668:Tcf3 protein, mouse