Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12)

The t(12;13)(p13;q12) is a rare, recurrent translocation reported in a rang e of hematological malignancies. We have analyzed the molecular basis of th is lesion in three patients with acute myeloid leukemia (AML), two of whom were known to have chromosome 12 breakpoints within the ETV6 gene. Fluoresc ence in situ hybridization (FISH) with ETV6 cosmids indicated that this gen e was also disrupted in the third patient, while the normal ETV6 allele was retained. 3' rapid amplification of cDNA ends (RACE) polymerase chain reac tion (PCR) from bone marrow mRNA of this individual identified a novel sequ ence fused to ETV6 that was homologous to a region just upstream of the mou se CDX2 homeobox gene, the human homologue of which has previously been map ped to chromosome 13q12. PCR primers designed to amplify an ETV6-CDX2 fusio n identified two major transcripts from this patient. First, a direct in-fr ame fusion between exon 2 of ETV6 and exon 2 of CDX2, and second, a transcr ipt that had an additional sequence of unknown origin spliced between these same exons. Surprisingly, apparently normal CDX2 transcripts, usually expr essed only in intestinal epithelium, were also detectable in cDNA from this patient. Neither normal nor fusion CDX2 mRNA was detectable in the two oth er patients with a t(12;13), indicating that this translocation is heteroge neous at the molecular revel. Reverse transcription-PCR analysis showed tha t CDX2 mRNA, but not ETV6-CDX2 mRNA, was strongly expressed in 1 of 10 pati ents with chronic myeloid leukemia in transformation, suggesting that dereg ulation of this gene may be more widespread in leukemia. CDX2 is known to r egulate class I homeobox genes and its expression in hematopoietic cells ma y critically alter the balance between differentiation and proliferation. ( C) 1999 by The American Society of Hematology.