Department of Pathology, University of Verona, Verona, Italy.
Cancer Res. 2009 Dec 15;69(24):9281-90. doi: 10.1158/0008-5472.CAN-09-2009.
Activation of lymphocyte function-associated antigen-1 (LFA-1) by chemokines is fine-tuned by inside-out signaling mechanisms responsible for integrin-mediated adhesion modulation. In the present study, we investigated the possibility of qualitative variability of signaling mechanisms controlling LFA-1 activation in chronic lymphocytic leukemia (CLL) cells. We pursued a multiplexed comparative analysis of the role of the recently described chemokine-triggered rho-signaling module in human normal versus CLL B-lymphocytes. We found that the rho-module of LFA-1 affinity triggering is functionally conserved in normal B-lymphocytes. In contrast, in malignant B-lymphocytes isolated from patients with B-CLL, the role of the rho-module was not maintained, showing remarkable differences and variability. Specifically, RhoA and phospholipase D1 were crucially involved in LFA-1 affinity triggering by CXCL12 in all analyzed patients. In contrast, Rac1 and CDC42 involvement displayed a consistent patient-by-patient variability, with a group of patients showing LFA-1 affinity modulation totally independent of Rac1 and CDC42 signaling activity. Finally, phosphatidylinositol-4-phosphate 5-kinase isoform 1gamma (PIP5KC) was found without any regulatory role in all patients. The data imply that the neoplastic progression may completely bypass the regulatory role of Rac1, CDC42, and PIP5KC, and show a profound divergence in the signaling mechanisms controlling integrin activation in normal versus neoplastic lymphocytes, suggesting that patients with CLL can be more accurately evaluated on the basis of the analysis of signaling mechanisms controlling integrin activation. Our findings could potentially affect the diagnosis, prognosis, and therapy of CLL disorders.
淋巴细胞功能相关抗原-1（LFA-1）的激活受化学趋化因子调节，这是一种负责整合素介导的黏附调节的细胞内信号机制。在本研究中，我们研究了控制慢性淋巴细胞白血病（CLL）细胞中 LFA-1 激活的信号机制是否存在定性变异性的可能性。我们采用了一种多重比较分析方法，研究了最近描述的化学趋化因子触发的 rho 信号模块在正常 B 淋巴细胞和 CLL B 淋巴细胞中的作用。我们发现，LFA-1 亲和力触发的 rho 模块在正常 B 淋巴细胞中具有功能保守性。相比之下，在从 B-CLL 患者中分离出的恶性 B 淋巴细胞中，rho 模块的作用没有得到维持，表现出显著的差异和可变性。具体来说，RhoA 和磷脂酶 D1 在所有分析的患者中都参与了 CXCL12 触发的 LFA-1 亲和力触发。相反，Rac1 和 CDC42 的参与表现出一致的患者间变异性，一组患者的 LFA-1 亲和力调节完全独立于 Rac1 和 CDC42 信号活性。最后，磷脂酰肌醇-4-磷酸 5-激酶同工型 1γ（PIP5KC）在所有患者中均未发现具有任何调节作用。这些数据表明，肿瘤的进展可能完全绕过 Rac1、CDC42 和 PIP5KC 的调节作用，并显示出在正常和肿瘤淋巴细胞中控制整合素激活的信号机制存在深刻的分歧，这表明可以根据控制整合素激活的信号机制分析更准确地评估 CLL 患者。我们的发现可能会对 CLL 疾病的诊断、预后和治疗产生影响。
