Cloning and characterization of the novel chimeric gene TEL/PTPRR in acute myelogenous leukemia with inv(12)(p13q13).
We have cloned a novel TEL/protein tyrosine phosphatase receptor-type R (PTPRR) chimeric gene generated by inv(12)(p13q13). PTPRR is the first protein tyrosine phosphatase identified as a fusion partner of TEL. The chimeric gene fused exon 4 of the TEL gene with exon 7 of the PTPRR gene, and produced 10 isoforms through alternative splicing. Two isoforms that were expressed at the highest level in the leukemic cells could have been translated into COOH-terminally truncated TEL protein possessing the helix-loop-helix domain (tTEL) and TEL/PTPRR chimeric protein linking the helix-loop-helix domain of TEL to the catalytic domain of PTPRR. These two mutant proteins exerted a dominant-negative effect over transcriptional repression mediated by wild-type TEL, although they themselves did not show any transcriptional activity. Heterodimerization with wild-type TEL might be an underlying mechanism in this effect. TEL/PTPRR did not exhibit any tyrosine phosphatase activity. Importantly, overexpression of TEL/PTPRR in granulocyte macrophage colony-stimulating factor-dependent UT7/GM cells resulted in their factor-independent proliferation, whereas overexpression of tTEL did not. After cytokine depletion, phosphorylated signal transducers and activators of transcription 3 (STAT3) significantly declined in mock cells, but remained in both tTEL- and TEL/PTPRR-overexpressing cells. Loss of tumor suppressive function of wild-type TEL and maintenance of STAT3-mediated signal could at least partly contribute to the leukemogenesis caused by inv(12)(p13q13).
Nakamura
Fumihiko
F
Department of Hematology, Dokkyo University School of Medicine, Tochigi, Japan.
Nakamura
Yuichi
Y
Maki
Kazuhiro
K
Sato
Yuko
Y
Mitani
Kinuko
K
D000328:Adult; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D007446:Chromosome Inversion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003001:Cloning, Molecular; D016384:Consensus Sequence; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D017027:Protein Tyrosine Phosphatases; D050783:Proto-Oncogene Proteins c-ets; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C513469:PTPRR protein, human; C513472:Ptprr protein, mouse