A pediatric case of acute megakaryocytic leukemia with double chimeric transcripts of CBFA2T3-GLIS2 and DHH-RHEBL1
A pediatric case of acute megakaryocytic leukemia with double chimeric transcripts of CBFA2T3-GLIS2 and DHH-RHEBL1
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CBFA2T3-GLIS2和DHH-RHEBL1双嵌合转录本的急性巨核细胞白血病儿科病例
DOI：
10.1080/10428194.2017.1387901
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Kawaguchi Hiroyuki
中科院分区：
文献类型：
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作者：
Mitsui-Sekinaka Kanako;Sekinaka Yujin;Ogura Yumi;Honda Mamoru;Ohyama Ryo;Oyama Chigusa;Isobe Kiyotaka;Mori Makiko;Arakawa Yuki;Koh Katsuyoshi;Hanada Ryoji;Nonoyama Shigeaki;Kawaguchi Hiroyuki
大约 20% 的儿童急性髓性白血病 (AML) 病例显示正常核型，在常规细胞遗传学分析中没有任何可识别的细胞遗传学改变。最近最先进的技术在这些细胞遗传学正常的白血病中揭示了几种以前未检测到的嵌合转录本。其中一个嵌合基因 CBFA2T3-GLIS2，由 CBFA2T3（核辅阻遏物 ETO 家族成员）和 GLIS2（转录因子 GLI 家族成员）融合而成，已在非唐氏综合症急性巨核细胞白血病 (AMkL) 以及其他一些非巨核细胞 AML 亚型中检测到 （FAB-M0、M1、M2、M4、M5、M5a）[1, 2]。已报道多个嵌合 CBFA2T3-GLIS2 转录本：CBFA2T3-ex10/GLIS2-ex3 [1]、CBFA2T3-ex10/GLIS2-ex2 和 CBFA2T3-ex11/GLIS2-ex3 [2]。尽管 CBFA2T3-GLIS2 阳性 AMkL 患者的预后非常差，但该疾病的发病机制在很大程度上仍不清楚。 Desert Hedgehog-Ras 同源物富含 Brain Like 1 (DHH-RHEBL1) 是另一种神秘的嵌合体转录物，涉及 Hedgehog 家族成员 DHH 和 Ras 家族的小型 GTP 酶 RHEBL1。这种嵌合转录本仅在 CBFA2T3-GLIS2 阳性白血病细胞中发现，并且发现这两种病理转录本呈阳性的患者的八年总生存率比不携带 DHH-RHEBL1 嵌合体的 CBFA2T3-GLIS2 重排患者差 [3]。第二个嵌合体的生物学机制和临床意义仍不清楚。一名原本健康、没有唐氏综合症的一岁女孩因低烧、面神经麻痹和左大腿实体瘤入院。入院前三天已出现发烧和麻痹症状，入院前一个月患者父母已发现肿瘤。正电子发射断层扫描-计算机断层扫描显示左乳突窦和颅内硬膜外间隙以及左大腿肌内间隙有多发肿瘤。骨髓 (BM) 抽吸显示髓过氧化物酶阴性母细胞，占所有有核细胞的 76.4%。这些胚细胞在形态上是不同的，因为它们的表面有气泡。对白血病细胞的流式细胞术分析显示，它们的 CD19、CD33、CD34、CD41、CD61 和 CD56 呈阳性。核型分析显示复杂的核型（补充表）。白血病细胞两者均呈阳性
Approximately 20% of the pediatric acute myeloid leukemia (AML) cases show normal karyotypes without any recognizable cytogenetic alteration on conventional cytogenetic analysis. Recent state-of-the-art techniques have unveiled several previously undetected chimera transcripts in these cytogenetically normal leukemias. One of those chimeric genes, CBFA2T3-GLIS2, formed by the fusion of CBFA2T3, a member of the ETO family of nuclear corepressors, and GLIS2, a member of the GLI family of transcription factors, has been detected in non-Down syndrome acute megakaryocytic leukemia (AMkL), as well as in some other non-megakaryoblastic AML subtypes (FAB-M0, M1, M2, M4, M5, M5a)[1, 2]. Multiple chimeric CBFA2T3-GLIS2 transcripts have been reported: CBFA2T3-ex10/GLIS2-ex3 [1], CBFA2T3-ex10/GLIS2-ex2, and CBFA2T3-ex11/GLIS2-ex3 [2]. Although patients with CBFA2T3-GLIS2-positive AMkL have a very poor prognosis, the pathogenesis of this disease largely remains unknown. Desert Hedgehog-Ras Homologue Enriched in Brain Like 1 (DHH-RHEBL1) is another cryptic chimera transcript involving DHH, a member of Hedgehog family, and RHEBL1, a small GTPase of the Ras family. This chimeric transcript is found exclusively in CBFA2T3-GLIS2-positive leukemic cells, and the eight-year overall survival rates of patients positive for both these pathological transcripts were found to be worse than those of CBFA2T3-GLIS2-rearranged patients not harboring the DHH-RHEBL1 chimera [3]. The biological mechanism and clinical significance of this second chimera remain unknown. A previously healthy one-year-old girl without Down syndrome was admitted for low-grade fever, facial nerve palsy, and solid tumor in her left thigh. The fever and palsy had manifested three days prior to admission, and the patientLs parents had recognized the tumor one month prior to admission. Positron emission tomography-computed tomography revealed multiple tumors in the left mastoid antrum and intracranial epidural space, as well as in the intramuscular space of the left thigh. Bone marrow (BM) aspiration revealed myeloperoxidase-negative blast cells, which constituted 76.4% of all nucleated cells. The blast cells were morphologically distinct in that they had blebs on their surface. Flow cytometry analysis of the leukemic cells revealed that they were positive for CD19, CD33, CD34, CD41, CD61, and CD56. Karyotype analysis showed complex karyotypes (Supplementary Table). The leukemic cells were positive for both