Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13).
The ETV6 gene (first identified as TEL) is a frequent target of chromosomal translocations in both myeloid and lymphoid leukemias. At present, more than 40 distinct translocations have been cytogenetically described, of which 13 have now also been characterized at the molecular level. These studies revealed the generation of in-frame fusion genes between different domains of ETV6 and partner genes encoding either kinases or transcription factors. However, in a number of cases-including a t(6;12)(q23;p13), the recurrent t(5;12)(q31;p13), and some cases of the t(4;12)(q11-q12;p13) described in this work-functionally significant fusions could not be identified, raising the question as to what leukemogenic mechanism is implicated in these cases. To investigate this, we have evaluated the genomic regions at 4q11-q12 and 5q31, telomeric to the breakpoints of the t(4;12)(q11-q12;p13) and t(5;12)(q31;p13). The homeobox gene GSH2 at 4q11-q12 and the IL-3/CSF2 locus at 5q31 were found to be located close to the respective breakpoints. In addition, GSH2 and IL-3 were found to be ectopically expressed in the leukemic cells, suggesting that expression of GSH2 and IL-3 was deregulated by the translocation. Our results indicate that, besides the generation of fusion transcripts, deregulation of the expression of oncogenes could be a variant leukemogenic mechanism for translocations involving the 5' end of ETV6, especially for those translocations lacking functionally significant fusion transcripts.
Cools
Jan
J
Human Genome Laboratory, Center for Human Genetics-Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Belgium.
Mentens
Nicole
N
Odero
Maria D
MD
Peeters
Pieter
P
Wlodarska
Iwona
I
Delforge
Michel
M
Hagemeijer
Anne
A
Marynen
Peter
P
D016475:3T3 Cells; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019457:Chromosome Breakage / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins / Q000235:genetics*; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics / Q000502:physiology; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007377:Interleukin-3; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C109498:Gsh2 protein, mouse; C491626:Gsx2 protein, human