Myklebust June H, Brody Joshua, Kohrt Holbrook E, Kolstad Arne, Czerwinski Debra K, Wälchli Sébastien, Green Michael R, Trøen Gunhild, Liestøl Knut, Beiske Klaus, Houot Roch, Delabie Jan, Alizadeh Ash A, Irish Jonathan M, Levy Ronald
Oncology Division, Department of Medicine, Stanford University, Stanford, CA.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Blood. 2017 Feb 9;129(6):759-770. doi: 10.1182/blood-2016-05-718494. Epub 2016 Dec 23.
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.
B细胞抗原受体（BCR）下游的激酶是非霍奇金淋巴瘤（NHL）治疗的有吸引力的靶点。由于临床反应各不相同，因此需要更好地了解个体患者中BCR信号传导的激活和调节情况。在这里，使用磷酸特异性流式细胞术从95名代表4种NHL类型的患者中获取恶性B细胞信号谱，揭示了慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）肿瘤之间的显著差异。弥漫性大B细胞淋巴瘤患者的淋巴瘤细胞大多数测量的信号节点具有高基础磷酸化水平，而滤泡性淋巴瘤细胞则呈现相反的模式，基础水平无或非常低。MCL在基础水平上显示出较大的患者间变异性，AKT、细胞外信号调节激酶、p38、STAT1和STAT5的磷酸化形式水平升高与不良预后相关。CLL肿瘤中BCR信号节点（Src家族酪氨酸激酶、脾酪氨酸激酶[SYK]、磷脂酶Cγ）的磷酸化形式基础水平升高，但α-BCR诱导的信号较低。这与MCL肿瘤形成对比，MCL肿瘤中α-BCR诱导的信号是可变的，但与其他类型相比显著增强。CD79B的过表达，结合一种门控策略，即根据CD79B水平直接量化每个细胞的信号输出，证实了表面CD79B、免疫球蛋白M（IgM）和IgM诱导的信号水平之间的直接关系。此外，α-BCR诱导的信号强度在患者样本中各不相同，与BCR亚基CD79B表达相关，但与MCL中对布鲁顿酪氨酸激酶（BTK）和SYK抑制剂的敏感性呈负相关。BCR水平和信号传导的这些个体差异可能与对BCR通路抑制剂的治疗反应差异有关。
