The first case of acute T-cell lymphoblastic leukemia containing the e19a2BCR-ABL1 tran a durable molecular response using imatinib-basedchemotherapy
The first case of acute T-cell lymphoblastic leukemia containing the e19a2BCR-ABL1 tran a durable molecular response using imatinib-basedchemotherapy
复制标题
首例含有 e19a2BCR-ABL1 的急性 T 细胞淋巴细胞白血病使用基于伊马替尼的化疗产生持久的分子反应
DOI：
10.1080/10428194.2016.1235275
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发表时间：
2016
影响因子：
2.6
通讯作者：
Yu Wu
中科院分区：
文献类型：
--
作者：
Wanhua Zhang;Yu Wu
有15-25%的成人急性淋巴细胞白血病（ALL）患者和3-4%的儿童ALL患者具有Ph染色体;该染色体由22号染色体上的BCR基因和9号染色体上的ABL 1癌基因之间的易位产生，其导致BCR/ABL 1融合基因。BCR基因内的断裂点主要定位于三个区域。主要断裂点簇区域（M-BCR）位于BCR基因的外显子12和16之间。涉及该区域的易位产生e13 a2或e14 a2转录物，其产生210-kDa蛋白（p210），其存在于大多数慢性粒细胞白血病（CML）患者和三分之一的Ph阳性ALL病例中。另一个断点位于外显子e2 0和e2之间的上游，称为次要断点簇区（m-BCR）;涉及该区域的易位产生e1 a2连接，该连接被翻译成较小的190 kDa蛋白（p190）。P190存在于三分之二的Ph阳性ALL患者和少数CML病例中。第三个罕见的微断裂点（μ-BCR）位于外显子19和20之间，编码一个230 kDa的大融合蛋白（p230）。在不到3%的CML患者中以及在极罕见的ALL和急性髓细胞白血病（AML）病例中观察到该断点。[1，2]通常，BCR-ABL 1融合基因见于B系ALL，但在T系ALL中罕见。根据我们对文献的回顾，仅报告了约30例原发性Ph阳性T细胞ALL。这些病例的分子亚型为e13 a2、e14 a2或e1 a2。罕见的e19 a2转录本从未在Ph阳性T细胞ALL中报道过。在这里，我们描述了第一例Ph阳性T细胞ALL与罕见的e19 a2 BCR-ABL 1融合转录。伊马替尼为基础的化疗诱导持久的分子反应，在这个病人。患者女，38岁，因左颈淋巴结肿大2个月于2015年6月入住我科。然后她出现头晕、发热和排痰性咳嗽。体格检查显示左颈淋巴结肿大，肋缘下5 cm处可触及肿大的脾脏。她否认有任何异常的外周血检查结果。最初的实验室检查显示外周血中的白色血细胞计数为82.46 109/L，原始细胞占54.0%，血红蛋白水平为109 g/L，血小板计数为112 109/L，乳酸脱氢酶水平为457 U/L。骨髓穿刺涂片显示73.0%的原始细胞浸润表现为淋巴样特征。流式细胞术显示原始细胞为CD 34阳性（67.3%），HLA-DR（71.2%），CD2（38.8%），胞浆CD 3（73.8%）、CD 4（9.3%）、CD 5（46.3%）、CD 7（74.3%）、CD 56（21.7%）和CD 117（12.4%），CD 1a、CD 19、cCD 79 a和cMPO阴性，与pro-T-ALL免疫表型一致。根据国际人类细胞遗传学命名系统（ISCN）2013（图1（A）），细胞遗传学分析显示复杂核型为48，XX，der（9）t（9; 22）（q34; q11），num 19，num 22）（q11）t（9; 22），nummar [20]。根据Pallisgaard等人开发的方法进行多重巢式逆转录-聚合酶链反应。[3]并检测到e19 a2 BCR/ABL 1融合转录物，而没有任何其它融合基因，如SIL-TAL 1、E2 A-PBX 1、HOX 11易位或其它（图1（B））。此外，未检测到IKZF 1的异常表达，这在B细胞ALL中常见。患者接受400 mg/天伊马替尼加CDVD（环磷酰胺，柔红霉素，长春地辛和地塞米松）治疗。
There are 15-25% of adult acute lymphoblastic leukemia (ALL) patients and 3-4% of pediatric ALL patients who have the Ph chromosome; this chromosome results from the translocation between the BCR gene on chromosome 22 and the ABL1 oncogene on chromosome 9, which leads to the BCR/ABL1 fusion gene. The breakpoints within the BCR gene primarily map to three regions. The major breakpoint cluster region (M-BCR) lies between exons 12 and 16 of the BCR gene. Translocations involving this region give rise to either e13a2 or e14a2 transcripts that generate a 210-kDa protein (p210), which is present in most patients with chronic myeloid leukemia (CML) and also in one-third of Ph-positive ALL cases. Another breakpoint is further upstream between exons e2 0 and e2 and is called the minor breakpoint cluster region (m-BCR); translocations involving this region yield an e1a2 junction that is translated into a smaller 190-kDa protein (p190). P190 is present in two-thirds of patients with Ph-positive ALL and in a few cases of CML. The third rare micro-breakpoint (μ-BCR) is localized between exons 19 and 20 and codes for a large 230-kDa fusion protein (p230). This breakpoint is observed in less than 3% of patients with CML and in extremely rare cases of ALL and acute myeloid leukemia (AML).[1, 2] Usually, the BCR-ABL1 fusion gene is observed in B-lineage ALL, but is rare in T-lineage ALL. According to our review of the literature, only approximately 30 cases of de novo Ph-positive T-cell ALL have been reported. The molecular subtypes of these cases were e13a2, e14a2, or e1a2. The rare e19a2 transcript has never been reported in Ph-positive T-cell ALL. Here, we describe the first case of Ph-positive T-cell ALL with the rare e19a2 BCR-ABL1 fusion transcript. Imatinib-based chemotherapy induced a durable molecular response in this patient. A 38-year-old female was admitted to our department in June 2015 with a 2-month history of enlargement of the left cervical lymph nodes. She then developed dizziness, fever, and a productive cough. Physical examination revealed enlarged left cervical lymph nodes and an enlarged spleen palpable 5cm below the costal margin. She denied having any prior abnormal peripheral blood test results. Initial laboratory studies revealed a white blood cell count of 82.46 Â 109/L with 54.0% blast cells in the peripheral blood, a hemoglobin level of 109g/L, a platelet count of 112Â109/L, and a lactate dehydrogenase level of 457U/L. Bone marrow aspiration smear revealed 73.0% blast cell infiltration exhibiting lymphoid features. Flow cytometry showed that the blasts were positive for CD34 (67.3%), HLA-DR (71.2%), CD2 (38.8%), cytoplasmic CD3 (73.8%), CD4 (9.3%), CD5 (46.3%), CD7 (74.3%), CD56 (21.7%), and CD117 (12.4%) and were negative for CD1a, CD19, cCD79a, and cMPO, which is consistent with a pro-T-ALL immunophenotype. Cytogenetic analysis revealed a complex karyotype that was 48, XX, der (9) t (9; 22)(q34; q11), þ19, idic (22)(q11) t (9; 22), þmar [20] according to the International System of Human Cytogenetic Nomenclature(ISCN) 2013 (Figure 1 (A)). Multiplex nested reverse transcription-polymerase chain reaction was performed according to the method developed by Pallisgaard et al.[3] and detected an e19a2 BCR/ABL1 fusion transcript without any other fusion genes such as SIL-TAL1, E2A-PBX1, HOX11 translocation, or others (Figure 1 (B)). Additionally, no abnormal expression of IKZF1, which is encountered frequently in B-cell ALL, was detected. The patient was treated with 400mg/day of imatinib plus CDVD (cyclophosphamide, daunorubicin, vindesine, and dexamethasone …