The ETS factor TEL2 is a hematopoietic oncoprotein.
TEL2/ETV7 is highly homologous to the ETS transcription factor TEL/ETV6, a frequent target of chromosome translocation in human leukemia. Although both proteins are transcriptional inhibitors binding similar DNA recognition sequences, they have opposite biologic effects: TEL inhibits proliferation while TEL2 promotes it. In addition, forced expression of TEL2 but not TEL blocks vitamin D3-induced differentiation of U937 and HL60 myeloid cells. TEL2 is expressed in the hematopoietic system, and its expression is up-regulated in bone marrow samples of some patients with leukemia, suggesting a role in oncogenesis. Recently we also showed that TEL2 cooperates with Myc in B lymphomagenesis in mice. Here we show that forced expression of TEL2 alone in mouse bone marrow causes a myeloproliferative disease with a long latency period but with high penetrance. This suggested that secondary mutations are necessary for disease development. Treating mice receiving transplants with TEL2-expressing bone marrow with the chemical carcinogen N-ethyl-N-nitrosourea (ENU) resulted in significantly accelerated disease onset. Although the mice developed a GFP-positive myeloid disease with 30% of the mice showing elevated white blood counts, they all died of T-cell lymphoma, which was GFP negative. Together our data identify TEL2 as a bona fide oncogene, but leukemic transformation is dependent on secondary mutations.
Carella
Cintia
C
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Potter
Mark
M
Bonten
Jacqueline
J
Rehg
Jerold E
JE
Neale
Geoffrey
G
Grosveld
Gerard C
GC
D000477:Alkylating Agents / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D005038:Ethylnitrosourea / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D015870:Gene Expression; D018922:HL-60 Cells; D006410:Hematopoiesis; D006801:Humans; D016399:Lymphoma, T-Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic / Q000235:genetics; D020298:U937 Cells; D000097764:ETS Translocation Variant 6 Protein
D000477:Alkylating Agents; D002273:Carcinogens; D005038:Ethylnitrosourea; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; C409823:ETV7 protein, human