Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.
Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.
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DOI：
10.1016/j.ccell.2015.02.003
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发表时间：
2015-03-09
期刊：
影响因子：
50.3
通讯作者：
Müschen M
中科院分区：
文献类型：
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作者：
Geng H;Hurtz C;Lenz KB;Chen Z;Baumjohann D;Thompson S;Goloviznina NA;Chen WY;Huan J;LaTocha D;Ballabio E;Xiao G;Lee JW;Deucher A;Qi Z;Park E;Huang C;Nahar R;Kweon SM;Shojaee S;Chan LN;Yu J;Kornblau SM;Bijl JJ;Ye BH;Ansel KM;Paietta E;Melnick A;Hunger SP;Kurre P;Tyner JW;Loh ML;Roeder RG;Druker BJ;Burger JA;Milne TA;Chang BH;Müschen M
研究了来自四项临床试验的830例前BALL病例，我们发现人类ALL可以根据前BCR功能分为两种基本不同的亚型。虽然在大多数ALL病例中不存在，但在112例（13.5%）病例中发现了紧张性前BCR信号传导。在这些情况下，紧张性前BCR信号传导诱导BCL6的活化，这进而在转录水平上增加前BCR信号传导输出。有趣的是，前BCR相关酪氨酸激酶的抑制减少了组成型BCL 6表达，并选择性地杀死患者来源的前BCR + ALL细胞。这些发现确定了人类ALL的遗传和表型不同的子集，其严重依赖于紧张性前BCR信号传导。体内治疗研究表明，前BCR酪氨酸激酶抑制剂可用于治疗前BCR + ALL患者。
Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.