Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment.
Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment.
复制标题
DOI：
10.1016/j.bbamcr.2015.07.009
复制
发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Burger JA
中科院分区：
文献类型：
--
作者：
Ten Hacken E;Burger JA
慢性淋巴细胞性白血病（CLL）是成熟B淋巴细胞的恶性肿瘤，其高度依赖于与组织微环境的相互作用来存活和增殖。微环境的关键组分是单核细胞衍生的nurselike细胞（NLC）、间充质基质细胞、T细胞和NK细胞，其通过粘附分子、趋化因子受体、肿瘤坏死因子（TNF）家族成员和可溶性因子的复杂网络与CLL细胞通信。（自身）抗原和/或自主机制激活次级淋巴组织中的B细胞受体（BCR）及其下游信号级联反应，在CLL中发挥核心致病作用。新型小分子抑制剂，包括布鲁顿酪氨酸激酶（BTK）抑制剂伊曲替尼和磷酸肌醇-3-激酶δ（PI 3 K δ）抑制剂艾代拉里斯，靶向BCR信号传导，并且已经成为该疾病中最成功的新疗法。我们在这里回顾CLL细胞的细胞和分子特征，并讨论与其微环境的串扰所涉及的细胞成分和关键途径。我们还强调了相关的新型治疗策略，重点是免疫调节剂和BCR信号抑制剂，以及这些治疗如何破坏CLL-微环境相互作用。
Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions.