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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1025-1031
Fusion of ETV6 to the Caudal-Related Homeobox Gene CDX2 in Acute
Myeloid Leukemia With the t(12;13)(p13;q12)
Andrew Chase,
Andreas Reiter,
Linda Burci,
Giovanni Cazzaniga,
Andrea Biondi,
Julie Pickard,
Irene A.G. Roberts,
John M. Goldman, and
Nicholas C.P. Cross
From the Department of Haematology, Imperial College School of
Medicine, Hammersmith Hospital, London, UK; and Clinica Pediatrica
Università di Milano, Ospedale San Gerardo, Monza, Italy.
The t(12;13)(p13;q12) is a rare, recurrent translocation reported in
a range of hematological malignancies. We have analyzed the molecular
basis of this lesion in three patients with acute myeloid leukemia
(AML), two of whom were known to have chromosome 12 breakpoints within
the ETV6 gene. Fluorescence in situ hybridization (FISH) with ETV6
cosmids indicated that this gene was also disrupted in the third
patient, while the normal ETV6 allele was retained. 3' rapid
amplification of cDNA ends (RACE) polymerase chain reaction (PCR) from
bone marrow mRNA of this individual identified a novel sequence fused
to ETV6 that was homologous to a region just upstream of the mouse CDX2
homeobox gene, the human homologue of which has previously been mapped
to chromosome 13q12. PCR primers designed to amplify an ETV6-CDX2
fusion identified two major transcripts from this patient. First, a
direct in-frame fusion between exon 2 of ETV6 and exon 2 of CDX2, and
second, a transcript that had an additional sequence of unknown origin
spliced between these same exons. Surprisingly, apparently normal CDX2
transcripts, usually expressed only in intestinal epithelium, were also
detectable in cDNA from this patient. Neither normal nor fusion CDX2
mRNA was detectable in the two other patients with a t(12;13),
indicating that this translocation is heterogeneous at the molecular
level. Reverse transcription-PCR analysis showed that CDX2 mRNA, but not ETV6-CDX2 mRNA, was strongly expressed in 1 of 10 patients with
chronic myeloid leukemia in transformation, suggesting that deregulation of this gene may be more widespread in leukemia. CDX2 is
known to regulate class I homeobox genes and its expression in
hematopoietic cells may critically alter the balance between differentiation and proliferation.
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