Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity.
Anaplastic large cell lymphomas are associated with chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene at 2p23 that result in the expression of novel chimeric ALK proteins with transforming properties. In most of these tumors, the t(2;5)(p23;q35) generates the NPM-ALK fusion gene. However, several studies have now demonstrated that genes other than NPM may be fused to the ALK gene. We have recently described two different ALK rearrangements involving the TRK-fused gene (TFG) in which the same portion of ALK was fused to different length fragments of the 5' TFG region. These two rearrangements encoded chimeric proteins of 85 kd (TFG-ALK(S)) and 97 kd (TFG-ALK(L)), respectively. In this study, we have identified a new ALK rearrangement in which the catalytic domain of ALK was fused to a larger fragment of the TFG gene (TFG-ALK(XL)), encoding for a fusion protein of 113 kd. Genomic analysis of these three TFG-ALK rearrangements revealed that the TFG breakpoints occur at introns 3, 4, and 5, respectively, whereas the ALK breakpoints always occur in the same intron. No homologous regions or known recombination sequences were found in these regions. Transfection experiments using NIH-3T3 fibroblasts showed a similar transforming efficiency of TFG-ALK variants compared with NPM-ALK. In addition, in common with NPM-ALK, the TFG-ALK proteins formed stable complexes with the signaling proteins Grb2, Shc, and PLC-gamma. In conclusion, these findings indicate that the TFG may use a variety of intronic breakpoints in ALK rearrangements generating fusion proteins of different molecular weights, but with similar transforming potential than NPM-ALK.
Hernández
Luis
L
Centro de Investigación delCáncer, Centro Superior de Investigaciones Científicas-University of Salamanca, Salamanca, Spain.
Beà
Sílvia
S
Bellosillo
Beatriz
B
Pinyol
Magda
M
Falini
Brunangelo
B
Carbone
Antonino
A
Ott
German
G
Rosenwald
Andreas
A
Fernández
Alberto
A
Pulford
Karen
K
Mason
David
D
Morris
Stephan W
SW
Santos
Eugenio
E
Campo
Elias
E
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002648:Child; D002678:Chimera / Q000502:physiology; D005260:Female; D051380:GRB2 Adaptor Protein; D015321:Gene Rearrangement; D014644:Genetic Variation; D016678:Genome; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009857:Oncogenes / Q000502:physiology; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014158:Transcription, Genetic / Q000502:physiology; D014178:Translocation, Genetic / Q000235:genetics*; D010738:Type C Phospholipases / Q000378:metabolism; D033921:Vesicular Transport Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000077548:Anaplastic Lymphoma Kinase; D051380:GRB2 Adaptor Protein; D007527:Isoenzymes; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D020794:Receptor Protein-Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C528024:SHC1 protein, human; C528034:Shc1 protein, mouse; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C484335:Tfg protein, mouse; C000626173:ALK protein, human; C000626174:Alk protein, mouse