The high proportion of long-term nonprogressors among chronic lymphocytic leukemia (CLL) patients suggests the existence of a regulatory network that restrains the proliferation of tumor B cells. The identification of molecular determinants composing such network is hence fundamental for our understanding of CLL pathogenesis. Based on our previous finding establishing a deficiency in the signaling adaptor p66Shc in CLL cells, we undertook to identify unique phenotypic traits caused by this defect. Here we show that a lack of p66Shc shapes the transcriptional profile of CLL cells and leads to an upregulation of the surface receptor ILT3, the immunoglobulin-like transcript 3 that is normally found on myeloid cells. The ectopic expression of ILT3 in CLL was a distinctive feature of neoplastic B cells and hematopoietic stem cells, thus identifying ILT3 as a selective marker of malignancy in CLL and the first example of phenotypic continuity between mature CLL cells and their progenitors in the bone marrow. ILT3 expression in CLL was found to be driven by Deltex1, a suppressor of antigen receptor signaling in lymphocytes. Triggering of ILT3 inhibited the activation of Akt kinase upon B-cell receptor (BCR) stimulation. This effect was achieved through the dynamic coalescence of ILT3, BCRs, and phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 into inhibitory clusters at the cell surface. Collectively, our findings identify ILT3 as a signature molecule of p66Shc deficiency in CLL and indicate that ILT3 may functionally contribute to a regulatory network controlling tumor progression by suppressing the Akt pathway.

中文翻译：

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异位 ILT3 控制 B 细胞慢性淋巴细胞白血病中 Akt 的 BCR 依赖性激活

慢性淋巴细胞白血病 (CLL) 患者中长期未进展者的高比例表明存在抑制肿瘤 B 细胞增殖的调节网络。因此，鉴定构成此类网络的分子决定因素对于我们了解 CLL 发病机制至关重要。基于我们之前的发现，确定 CLL 细胞中信号适配器 p66Shc 存在缺陷，我们着手确定由该缺陷引起的独特表型特征。在这里，我们表明缺乏 p66Shc 会影响 CLL 细胞的转录谱，并导致表面受体 ILT3（通常在骨髓细胞上发现的免疫球蛋白样转录物 3）上调。ILT3 在 CLL 中的异位表达是肿瘤性 B 细胞和造血干细胞的一个显着特征，因此，将 ILT3 鉴定为 CLL 恶性肿瘤的选择性标记物，以及成熟 CLL 细胞与其骨髓祖细胞之间表型连续性的第一个例子。发现 CLL 中的 ILT3 表达由 Deltex1 驱动，Deltex1 是淋巴细胞中抗原受体信号传导的抑制因子。ILT3 的触发抑制了 B 细胞受体 (BCR) 刺激后 Akt 激酶的激活。这种效果是通过 ILT3、BCR 和磷脂酰肌醇-3,4,5-三磷酸 5-磷酸酶 1 在细胞表面动态聚结成抑制簇来实现的。总的来说，我们的研究结果将 ILT3 鉴定为 CLL 中 p66Shc 缺陷的标志分子，并表明 ILT3 可能通过抑制 Akt 途径在功能上有助于控制肿瘤进展的调节网络。