CLCA2, a novel RUNX1 partner gene in a therapy-related leukemia with t(1;21)(p22;q22).

The RUNX1 gene is frequently rearranged in de novo and therapy-related leukemia. In the present study, we identified the CLCA2 gene as a novel fusion partner of RUNX1 in a case of therapy-related acute myeloid leukemia associated with t(1;21)(p22;q22). Reverse transcriptase-polymerase chain reaction analysis and sequencing revealed that the t(1;21) results in out-of-frame RUNX1-CLCA2 fusions. Alternative splicing generates at least six fusion transcripts, including a major transcript fusing RUNX1 exon 6 with CLCA2 exon 2. These out-of-frame fusions produce putative truncated RUNX1 isoforms retaining the DNA binding Runt domain but not the transcriptional regulatory domain of RUNX1. No mutations were found in the exons encoding the Runt and C-terminal domains of the nonrearranged RUNX1 gene. Similar to truncated RUNX1 isoforms previously described, these shortened products could act as dominant negative inhibitors of RUNX1-dependent transactivation. CLCA2 is a breast tumor suppressor gene that encodes a member of the calcium-activated chloride channel family and is involved for the first time in a chromosomal translocation. The RUNX1-CLCA2 fusion is another example of out-of-frame fusion generating truncated RUNX1 isoforms that represent a recurrent molecular mechanism in RUNX1-related leukemias.