Packham Graham, Krysov Serge, Allen Alex, Savelyeva Natalia, Steele Andrew J, Forconi Francesco, Stevenson Freda K
Cancer Research UK Centre, Faculty of Medicine, University of Southampton, UK.
Cancer Research UK Centre, Faculty of Medicine, University of Southampton, UK
Haematologica. 2014 Jul;99(7):1138-48. doi: 10.3324/haematol.2013.098384.
Biologists and clinicians agree that the B-cell receptor influences the behavior of chronic lymphocytic leukemia, and promising new drugs are aimed at receptor-associated kinases. Engagement of surface immunoglobulin by antigen is a key driver of malignant cells with outcome influenced by the nature of the cell, the level of stimulation and the microenvironment. Analysis of surface immunoglobulin-mediated signaling in the two major disease subsets defined by IGHV mutational status reveals bifurcation of responses toward proliferation or anergy. Mutated chronic lymphocytic leukemia, generally of relatively good prognosis, is mainly, but not exclusively, driven towards anergy in vivo. In contrast, unmutated chronic lymphocytic leukemia shows less evidence for anergy in vivo retaining more responsiveness to surface immunoglobulin M-mediated signaling, possibly explaining increased tumor progression. Expression and function of surface immunoglobulin M in unmutated chronic lymphocytic leukemia appear rather homogeneous, but mutated chronic lymphocytic leukemia exhibits a highly heterogeneous profile that may relate to further variable clinical behavior within this subset. Anergy should increase susceptibility to apoptosis but, in leukemic cells, this may be countered by overexpression of the B-cell lymphoma-2 survival protein. Maintained anergy spreads to chemokines and adhesion molecules, restraining homing and migration. However, anergy is not necessarily completely benign, being able to reverse and regenerate surface immunoglobulin M-mediated responses. A two-pronged attack on proliferative and anti-apoptotic pathways may succeed. Increased understanding of how chronic lymphocytic leukemia cells are driven to anergy or proliferation should reveal predictive biomarkers of progression and of likely response to kinase inhibitors, which could assist therapeutic decisions.
生物学家和临床医生一致认为，B细胞受体影响慢性淋巴细胞白血病的行为，并且有前景的新药针对与受体相关的激酶。抗原与表面免疫球蛋白的结合是恶性细胞的关键驱动因素，其结果受细胞性质、刺激水平和微环境的影响。对由IGHV突变状态定义的两个主要疾病亚组中表面免疫球蛋白介导的信号传导的分析揭示了对增殖或无反应的反应分歧。突变的慢性淋巴细胞白血病通常预后相对较好，在体内主要但并非唯一地趋向于无反应。相比之下，未突变的慢性淋巴细胞白血病在体内显示出较少的无反应证据，对表面免疫球蛋白M介导的信号传导保持更高的反应性，这可能解释了肿瘤进展的增加。未突变的慢性淋巴细胞白血病中表面免疫球蛋白M的表达和功能似乎相当均匀，但突变的慢性淋巴细胞白血病表现出高度异质性的特征，这可能与该亚组内进一步可变的临床行为有关。无反应应增加对凋亡的易感性，但在白血病细胞中，这可能被B细胞淋巴瘤-2生存蛋白的过表达所抵消。维持的无反应扩散到趋化因子和黏附分子，抑制归巢和迁移。然而，无反应不一定完全无害，它能够逆转并重新产生表面免疫球蛋白M介导的反应。对增殖和抗凋亡途径的双管齐下攻击可能会成功。对慢性淋巴细胞白血病细胞如何被驱动至无反应或增殖的进一步了解，应该能够揭示疾病进展和对激酶抑制剂可能反应的预测性生物标志物，这有助于治疗决策。
