Defective expression of Bruton's tyrosine kinase in acute lymphoblastic leukemia
Defective expression of Bruton's tyrosine kinase in acute lymphoblastic leukemia
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DOI：
10.1080/1042819031000067576
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发表时间：
2003-01-01
影响因子：
2.6
通讯作者：
Uckun, FM
中科院分区：
文献类型：
--
作者：
Goodman, PA;Wood, CM;Uckun, FM
布鲁顿酪氨酸激酶 (BTK) 是一种细胞质酪氨酸激酶，在 B 细胞信号传导和发育中发挥重要作用。我们检查了新诊断的急性淋巴细胞白血病 (ALL) 婴儿 (N = 14) 和新诊断 (N = 10) 或复发 (N = 5) B 系 ALL 儿科患者的原代白血病细胞的 BTK 表达谱。对婴儿患者细胞 (N = 14) 中 BTK 蛋白和 mRNA 表达的分析显示，BTK 表达水平各不相同，大多数样本已减少至不存在 BTK 表达。对婴儿白血病细胞 Btk mRNA 的逆转录酶聚合酶链反应 (RT-PCR) 产物进行序列分析，发现存在异常转录本。这些 Btk 转录物的特征是单独删除外显子 16 (Delta16) 或同时删除外显子 15 和 16 (Delta15 和 16)。这些缺失涉及精确的外显子跳跃，并编码带有缺失（Delta16）或截短（Delta15 和 16）激酶结构域的 BTK 蛋白。将这些 Btk 转录本测序研究扩展到 15 名儿科 B 系 ALL 患者，发现几名儿科患者表达了外显子 16 缺失的 Btk 转录本，然而，这些儿科患者均未表达外显子 15 和 16 缺失的转录本。 Btk 信息表达的减少和异常删除的 Btk 转录本的表达都将导致 B 系白血病细胞中 BTK 蛋白表达和功能的减少。由于 BTK 是辐射诱导细胞凋亡所必需的，因此婴儿 ALL 细胞中功能性 BTK 表达减少至缺失可能有助于其抗辐射性。
Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that serves an essential role in B cell signaling and development. We examined the BTK expression profile of primary leukemic cells from infants with newly diagnosed acute lymphoblastic leukemia (ALL) (N = 14) and from pediatric patients with newly diagnosed (N = 10) or relapsed (N = 5) B-lineage ALL. Analysis of BTK protein and mRNA expression in the infant patient cells (N = 14) showed variable levels of BTK expression with the majority of samples having reduced to absent BTK expression. Sequence analysis of reverse transcriptase-polymerase chain reaction (RT-PCR) products of Btk mRNA from infant leukemia cells revealed the presence of aberrant transcripts. These Btk transcripts were characterized by either deletion of exon 16 (Delta16) alone or deletion of both exons 15 and 16 (Delta15 and 16). These deletions involve exact exon skipping and encode BTK proteins with either a deleted (Delta16), or truncated (Delta15 and 16) kinase domain. Extension of these Btk transcript sequencing studies to 15 pediatric B-lineage ALL patients revealed expression of exon 16 deleted Btk transcripts in several pediatric patients, however, none of these pediatric patients expressed transcripts with the exon 15 and 16 deletion. Both reduced expression of Btk message and expression of aberrant deleted Btk transcripts would contribute to reduced BTK protein expression and function in B-lineage leukemia cells. Since BTK is required for radiation induced apoptosis, reduced to absent expression of functional BTK in infant ALL cells could contribute to their radiation resistance.