Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression.
The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression of TCL1 leads to mature T cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, E mu-TCL1, established with TCL1 under the control of a V(H) promoter-Ig(H)-E mu enhancer to target TCL1 expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5(+) population in the peritoneal cavity of E mu-TCL1 mice starting at 2 mo of age that becomes evident in the spleen by 3-5 mo and in the bone marrow by 5-8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5(+) B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis.
Bichi
Roberta
R
Kimmel Cancer Center, Jefferson Medical College, 233 South 10th Street, Philadelphia, PA 19107, USA.
Shinton
Susan A
SA
Martin
Eric S
ES
Koval
Anatoliy
A
Calin
George A
GA
Cesari
Rossano
R
Russo
Giandomenico
G
Hardy
Richard R
RR
Croce
Carlo M
CM
D000375:Aging; D000818:Animals; D018956:CD5 Antigens; D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D016193:G1 Phase; D018390:Gene Targeting; D006801:Humans; D007124:Immunoenzyme Techniques; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids; D011518:Proto-Oncogene Proteins; D016192:Resting Phase, Cell Cycle; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018956:CD5 Antigens; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; C490393:Tcl1 protein, mouse; D014157:Transcription Factors