Increased autocrine interleukin‐6 production is significantly associated with worse clinical outcome in patients with chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) remains incurable with current standard therapy. We have previously reported that an increased expression of interleukin‐6 (IL‐6) receptor CD126 leads to resistance of CLL cells to chemotherapy and worse prognosis for patients with CLL. In this study, we determine whether autocrine IL‐6 production by CLL B cells is associated with poor clinical outcome and explore IL‐6‐mediated survival mechanism in primary CLL cells. Our results demonstrate that higher levels of autocrine IL‐6 are significantly associated with shorter absolute lymphocyte doubling time, patients received treatment, without complete remission, advanced Binet stages, 17p/11q deletion, and shorter time to first time treatment and progression‐free survival. IL‐6 activated both STAT3 and nuclear factor kappa B (NF‐κB) in primary CLL cells. Blocking IL‐6 receptor and JAK2 inhibited IL‐6‐mediated activation of STAT3 and NF‐κB. Our study demonstrates that an increased autocrine IL‐6 production by CLL B‐cells are associated with worse clinical outcome for patients with CLL. IL‐6 promotes CLL cell survival by activating both STAT3 and NF‐κB through diverse signaling cascades. Neutralizing IL‐6 or blocking IL‐6 receptor might contribute overcoming the resistance of CLL cells to chemotherapy. We propose that the measurement of autocrine IL‐6 could be a useful approach to predict clinical outcome.

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…Besides, some other serum markers have also been suggested in recent years. The measurement of autocrine interleukin-6 (IL-6) could be a useful approach to predict clinical outcomes [25]. Higher serum copper level predicts a shorter time to start treatment and poor response to treatment.…”

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

“…IL-6 could ameliorate B-CLL cells' survival by activating STAT3 and NK-kB. The blockage of IL-6 or its receptor could alleviate the problem of B-CLL resistance to the treatment [36].…”

Transferrin-Bound Doxorubicin Enhances Apoptosis and DNA Damage through the Generation of Pro-Inflammatory Responses in Human Leukemia Cells

“…IL-6 is known to activate both STAT3 and NF-κB in primary chronic lymphocytic leukemia (CLL) cells. The IL-6 production by CLL B-cells is associated with worse clinical outcome for patients with CLL [ 40 ]. Regarding the connection between the cytotoxicity of DOX and IL-6 production, it was found that IL-6 was significantly up-regulated in DOX-treated tissues and cells [ 41 ].…”