Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia.
Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia.
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慢性淋巴细胞白血病中涉及 YPEL5 和 PPP1CB 的反复 RNA 嵌合体。
DOI：
10.1073/pnas.1214326110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Elenitoba-Johnson
中科院分区：
文献类型：
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作者：
Velusamy,Thirunavukkarasu;Palanisamy,Nallasivam;Kalyana-Sundaram,Shanker;Sahasrabuddhe,AnaghAnant;Maher,ChristopherA;Robinson,DanielR;Bahler,DavidW;Cornell,TimothyT;Wilson,ThomasE;Lim,MeganS;Chinnaiyan,ArulM;Elenitoba-Johnson
慢性淋巴细胞白血病（CLL）是西半球成人最常见的白血病形式。肿瘤特异性染色体易位，在几种人类恶性肿瘤中的特征性发现，直接导致恶性转化，尚未在CLL中确定。使用配对末端转录组测序，我们确定了复发性和互惠RNA嵌合体，涉及Yippee样5（YPEL 5）和丝氨酸/苏氨酸蛋白磷酸酶PP 1-β-催化亚基（PPP 1CB）在CLL。在我们的初步筛选中，七个指标病例中有两个（28%）携带相互RNA嵌合体。采用实时定量PCR（q-real-time PCR），在103例CLL样本中有97例（95%）检测到YPEL 5/PPP 1CB和PPP 1CB/YPEL 5融合转录本，但在配对的正常样本、良性淋巴细胞或各种无关的癌症中均未检测到。全基因组测序和Southern杂交结果表明，YPEL 5和PPP 1CB之间没有基因组融合的证据。YPEL 5/PPP 1CB嵌合体在导入哺乳动物细胞后，表达一个截短的PPP 1CB蛋白，其磷酸酶活性降低。PPP 1CB沉默导致MEC 1和JVM 3细胞的增殖和集落形成增强，这意味着在成熟B细胞白血病的发病机制中的作用。这些研究揭示了涉及磷酸酶的复发性RNA嵌合体在一种常见形式的白血病发病机制中的潜在作用。
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR),YPEL5/PPP1CBandPPP1CB/YPEL5fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion betweenYPEL5andPPP1CB.YPEL5/PPP1CBchimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.