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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1776-1784
NEOPLASIA
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)
Jan Cools,
Nicole Mentens,
Maria D. Odero,
Pieter Peeters,
Iwona Wlodarska,
Michel Delforge,
Anne Hagemeijer, and
Peter Marynen
From the Human Genome Laboratory, Center for Human
Genetics Flanders Interuniversity Institute for Biotechnology (VIB),
and the Department of Hematology, University of Leuven, Belgium; and
the Department of Genetics, University of Navarra, Pamplona,
Spain.
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 casesincluding 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 workfunctionally 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.
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