Giguère Amélie, Hébert Josée
Quebec Leukemia Cell Bank and Hematology-Oncology Division, Maisonneuve-Rosemont Hospital, Montréal, Canada.
Cancer Genet Cytogenet. 2010 Oct 15;202(2):94-100. doi: 10.1016/j.cancergencyto.2010.07.116.
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.
RUNX1基因在原发性和治疗相关白血病中常发生重排。在本研究中，我们在1例与t(1;21)(p22;q22)相关的治疗相关急性髓系白血病病例中，鉴定出CLCA2基因为RUNX1的一个新的融合伴侣。逆转录聚合酶链反应分析和测序显示，t(1;21)导致了移码的RUNX1-CLCA2融合。可变剪接产生至少6种融合转录本，包括一种将RUNX1外显子6与CLCA2外显子2融合的主要转录本。这些移码融合产生了推定的截短RUNX1异构体，保留了DNA结合Runt结构域，但没有保留RUNX1的转录调节结构域。在未重排的RUNX1基因编码Runt和C末端结构域的外显子中未发现突变。与先前描述的截短RUNX1异构体相似，这些缩短的产物可作为RUNX1依赖性反式激活的显性负抑制剂。CLCA2是一种乳腺肿瘤抑制基因，编码钙激活氯通道家族的一个成员，并且首次参与染色体易位。RUNX1-CLCA2融合是产生截短RUNX1异构体的移码融合的另一个例子，这代表了RUNX1相关白血病中的一种常见分子机制。
