Zheng M, Turton K B, Zhu F, Li Y, Grindle K M, Annis D S, Lu L, Drennan A C, Tweardy D J, Bharadwaj U, Mosher D F, Rui L
Division of Hematology-Oncology, Department of Medicine, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oncogenesis. 2016 Jan 4;4(1):e184. doi: 10.1038/oncsis.2015.44.
Activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) is characterized by increased expression and activator of signal transducer and activator of transcription 3 (STAT3). ABC DLBCL cells require STAT3 for growth in culture. In ABC DLBCL cells, eosinophils and perhaps all cells, four variant STAT3 mRNAs (Sα, ΔSα, Sβ and ΔSβ) are present as a result of two alternative splicing events, one that results in the inclusion of a 55-residue C-terminal transactivation domain (α) or a truncated C-terminal domain with 7 unique residues (β) and a second that includes (S) or excludes (ΔS) the codon for Ser-701 in the linker between the SH2 and C-terminal domains. A substantial literature indicates that both α and β variants are required for optimal STAT3 function, but nothing is known about functions of ΔS variants. We used a knockdown/re-expression strategy to explore whether survival of ABC DLBCL cells requires that the four variants be in an appropriate ratio. No single variant rescued survival as well as STAT3Sα-C, Sα with activating mutations (A661C and N663C) in the SH2 domain. Better rescue was achieved when all four variants were re-expressed or Sα and ΔSα or Sβ and ΔSβ were re-expressed in pairs. Rescue correlated with expression of STAT3-sensitive genes NFKBIA and NFKBIZ. We consider a variety of explanations why a mix of S and ΔS variants of STAT3 should enable survival of ABC DLBCL cells.
活化B细胞样弥漫性大B细胞淋巴瘤（ABC DLBCL）的特征是信号转导子和转录激活子3（STAT3）的表达增加及激活。ABC DLBCL细胞在培养中生长需要STAT3。在ABC DLBCL细胞中，由于两个可变剪接事件，嗜酸性粒细胞以及可能所有细胞中存在四种可变STAT3 mRNA（Sα、ΔSα、Sβ和ΔSβ），一个事件导致包含一个55个残基的C末端反式激活结构域（α）或一个具有7个独特残基的截短C末端结构域（β），另一个事件包括（S）或排除（ΔS）SH2结构域与C末端结构域之间连接区中Ser-701的密码子。大量文献表明，α和β变体对于最佳STAT3功能都是必需的，但关于ΔS变体的功能一无所知。我们采用敲低/重新表达策略来探究ABC DLBCL细胞的存活是否要求这四种变体处于适当比例。没有单个变体能像STAT3Sα-C（SH2结构域具有激活突变（A661C和N663C）的Sα）那样挽救细胞存活。当重新表达所有四种变体或成对重新表达Sα和ΔSα或Sβ和ΔSβ时，能实现更好的挽救效果。挽救效果与STAT3敏感基因NFKBIA和NFKBIZ的表达相关。我们考虑了多种解释，说明为什么STAT3的S和ΔS变体组合应能使ABC DLBCL细胞存活。
