Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia.
Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia.
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DOI：
10.1016/j.celrep.2019.06.069
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发表时间：
2019-07-23
期刊：
影响因子：
8.8
通讯作者：
Altan-Bonnet G
中科院分区：
文献类型：
--
作者：
Ziegler CGK;Kim J;Piersanti K;Oyler-Yaniv A;Argyropoulos KV;van den Brink MRM;Palomba ML;Altan-Bonnet N;Altan-Bonnet G
在癌症生物学中，基因组改变的功能解释对于实现临床基因组分析的承诺至关重要。慢性淋巴细胞白血病（CLL）是一种B淋巴细胞在组成型B细胞受体（BCR）刺激下成熟的异质性疾病，多种克隆突变的功能作用在很大程度上仍然未知。在这里，我们证明了BCR信号动力学的改变是B细胞向恶性肿瘤发展的基础。我们揭示了原发性CLL B细胞BCR信号通路中出现的动态特征——双峰性、超敏性和迟滞性。通过单细胞磷酸化反应分析、计算模型和超分辨率成像证明，CLL中的这些信号异常定量地源于BCR聚类和具有正反馈强化的构成信号。这种失调的信号通过疾病严重程度和临床表现来区分CLL患者。这些发现为评估复杂和异质性白血病病理提供了定量框架和方法，并为与基因组分析并行的治疗策略提供了信息。Ziegler等人利用磷酸流式细胞术和计算模型发现，B细胞受体聚集和SYK和LYN的正反馈驱动慢性淋巴细胞白血病B细胞的信号超敏性、双稳定性和迟滞性。超分辨率显微镜证实了白血病B细胞的膜自聚集，信号功能障碍的变异性预测了疾病的严重程度。
In cancer biology, the functional interpretation of genomic alterations is critical to achieve the promise of genomic profiling in the clinic. For chronic lymphocytic leukemia (CLL), a heterogeneous disease of B-lymphocytes maturing under constitutive B cell receptor (BCR) stimulation, the functional role of diverse clonal mutations remains largely unknown. Here, we demonstrate that alterations in BCR signaling dynamics underlie the progression of B cells toward malignancy. We reveal emergent dynamic features—bimodality, hypersensitivity, and hysteresis—in the BCR signaling pathway of primary CLL B cells. These signaling abnormalities in CLL quantitatively derive from BCR clustering and constitutive signaling with positive feedback reinforcement, as demonstrated through single-cell analysis of phospho-responses, computational modeling, and super-resolution imaging. Such dysregulated signaling segregates CLL patients by disease severity and clinical presentation. These findings provide a quantitative framework and methodology to assess complex and heterogeneous leukemia pathology and to inform therapeutic strategies in parallel with genomic profiling. Using phospho-flow cytometry and computational modeling, Ziegler et al. find that B cell receptor clustering and positive feedback through SYK and LYN drive signaling hypersensitivity, bistability, and hysteresis in chronic lymphocytic leukemic B cells. Super-resolution microscopy confirms membrane auto-aggregation in leukemic B cells, and variability in signaling dysfunction predicts disease severity.
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DOI：
10.1126/science.1213368
发表时间：
2012-06-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Khalil AM;Cambier JC;Shlomchik MJ
通讯作者：
Shlomchik MJ
DOI：
10.1084/jem.20121801
发表时间：
2013-01-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hoogeboom R;van Kessel KP;Hochstenbach F;Wormhoudt TA;Reinten RJ;Wagner K;Kater AP;Guikema JE;Bende RJ;van Noesel CJ
通讯作者：
van Noesel CJ
影响因子：
16.6
作者：
de Castro, Maria Angela Gomes;Wildhagen, Hanna;Opazo, Felipe
通讯作者：
Opazo, Felipe
影响因子：
64.8
作者：
Duehren-von Minden, Marcus;Uebelhart, Rudolf;Jumaa, Hassan
通讯作者：
Jumaa, Hassan
影响因子：
3.4
作者：
Ketchum, Christina;Miller, Heather;Upadhyaya, Arpita
通讯作者：
Upadhyaya, Arpita