Department of Hematology, Oncology and Clinical Immunology and Rheumatology, University of Tübingen, Tübingen, Germany.
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tübingen, Tübingen, Germany.
Front Immunol. 2020 Sep 2;11:1995. doi: 10.3389/fimmu.2020.01995. eCollection 2020.
Most patients with chronic lymphocytic leukemia (CLL) exhibit an indolent disease course and unresponsive B cell receptors (BCRs) exemplified by an anergic phenotype of their leukemic cells. In up to 5% of patients, CLL transforms from an indolent subtype to an aggressive form of B cell lymphoma (Richter's syndrome), which is associated with worse disease outcome and severe downregulation of NFAT2. Here we show that ablation of the tyrosine kinase LCK, which has previously been characterized as a main NFAT2 target gene in CLL, leads to loss of the anergic phenotype, thereby restoring BCR signaling, which results in an acceleration of CLL. Our study identifies LCK as a main player in mediating BCR unresponsiveness and its role as a crucial regulator of anergy in CLL.
大多数慢性淋巴细胞白血病 (CLL) 患者表现出惰性疾病过程和无反应的 B 细胞受体 (BCR)，其白血病细胞表现出无反应性表型。在多达 5%的患者中，CLL 从惰性亚型转变为侵袭性 B 细胞淋巴瘤（里希特综合征），这与更差的疾病结局和 NFAT2 的严重下调有关。在这里，我们表明，先前被表征为 CLL 中 NFAT2 的主要靶基因的酪氨酸激酶 LCK 的缺失会导致无反应性表型的丧失，从而恢复 BCR 信号转导，从而加速 CLL 的发展。我们的研究将 LCK 鉴定为介导 BCR 无反应性的主要参与者及其在 CLL 中作为无反应性关键调节剂的作用。
