A novel TRB@/NOTCH1fusion gene in T-cell lymphoblastic lymphoma with t
A novel TRB@/NOTCH1fusion gene in T-cell lymphoblastic lymphoma with t
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T 细胞淋巴母细胞淋巴瘤中一种新型 TRB@/NOTCH1 融合基因
DOI：
10.1111/ejh.12019
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Minami H.
中科院分区：
文献类型：
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作者：
Yamamoto K;Nakamachi Y;Yakushijin K;Miyata Y;Okamura A;Kawano S;Matsuoka H;Minami H.
背景：在T细胞急性淋巴细胞白血病/淋巴瘤（T‐ALL/LBL）中，notch1的激活突变在超过50%的病例中被观察到，而涉及notch1at 9q34 andTRB@at 7q34的T (7;9)（q34;q34）是一种极其罕见但反复发生的易位。患者：41岁男性，纵膈肿物大，胸膜积液，淋巴结肿大，诊断为T - LBL。淋巴瘤细胞CD4、CD8、CD2、CD3、CD5、CD7、CD10和TdT均呈阳性。结果：胸膜积液细胞的G带和谱核型为47、XY、dup(1)（q21q32）、t(7;9)（q34;q34）、+20。基因组聚合酶链反应（PCR）显示，5 ‘端ofTRB@J1‐5与notch1exon 25的中间（5 ’端下游434 bp）在der(9)t（7;9）上以“头对头”的结构连接（7;9），尽管两个基因之间插入了9个额外的碱基。逆转录- PCR证实trb @/ notch1融合转录物的表达。同样，J1‐5的5 '端与缩短的外显子25融合，增加了9个碱基。小鼠T‐ALL外显子25的notch1断点非常接近缺失notch1的转录起始位点。结论：trb @/ notch1融合基因在25号外显子上有anotch1断点，这在其他4例t患者中未被发现（7;9），可能导致truncatedNOTCH1byTRB@enhancer元件的异常表达。由此产生的NOTCH1受体删除大部分细胞外结构域可能与T - LBL的发病机制有关，通过配体独立的NOTCH1途径的组成性激活，提示未来使用γ -分泌酶抑制剂治疗的途径。
Background: In T‐cell acute lymphoblastic leukemia/lymphoma (T‐ALL/LBL), activating mutations ofNOTCH1are observed in more than 50% of cases, whereas the t(7;9)(q34;q34) involvingNOTCH1at 9q34 andTRB@at 7q34 is an extremely rare but recurrent translocation.Patient: A 41‐year‐old male with a large mediastinal mass, pleural effusion, and lymphadenopathy was diagnosed as having T‐LBL. Lymphoma cells were positive for CD4, CD8, CD2, CD3, CD5, CD7, CD10, and TdT.Results: G‐banding and spectral karyotyping of pleural effusion cells showed 47,XY,dup(1)(q21q32),t(7;9)(q34;q34),+20. Genomic polymerase chain reaction (PCR) revealed that the 5′ end ofTRB@J1‐5 was connected with the middle ofNOTCH1exon 25 (434 bp downstream from its 5′ end) in a ‘head‐to‐head’ configuration on the der(9)t(7;9), although nine extra bases were inserted between the two genes. Reverse transcription‐PCR confirmed expression of theTRB@/NOTCH1fusion transcripts. Similarly, the 5′ end of J1‐5 was fused to the shortened exon 25 with nine extra bases. TheNOTCH1breakpoint in exon 25 was very close to transcription start sites of deletedNotch1in murine T‐ALL.Conclusions: TheTRB@/NOTCH1fusion gene with aNOTCH1breakpoint in exon 25, which has not previously been detected in four other reported cases with t(7;9), could lead to aberrant expression of the truncatedNOTCH1byTRB@enhancer elements. The resultant NOTCH1 receptor deleting most of the extracellular domain may be implicated in the pathogenesis of T‐LBL by ligand‐independent, constitutive activation of the NOTCH1 pathway, suggesting avenues for future therapy with γ‐secretase inhibitors.