Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, The Netherlands; Lymphoma and Myeloma Center, Amsterdam.
Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Department of Clinical Pathology, S.M. Goretti Hospital, Latina.
Haematologica. 2024 Jan 1;109(1):151-162. doi: 10.3324/haematol.2023.282760.
CD40 signaling upregulates BCL-XL and MCL-1 expression in the chronic lymphocytic leukemia (CLL) lymph node microenvironment, affording resistance to the BCL-2 inhibitor, venetoclax. Venetoclax resistance in the therapeutic setting and after long-term laboratory selection has been linked to metabolic alterations, but the underlying mechanism(s) are unknown. We aimed here to discover how CD40 stimulation as a model for tumor microenvironment-mediated metabolic changes, affects venetoclax sensitivity/resistance. CD40 stimulation increased oxidative phosphorylation and glycolysis, but only inhibition of oxidative phosphorylation countered venetoclax resistance. Furthermore, blocking mitochondrial import of pyruvate, glutamine or fatty acids affected CLL metabolism, but did not prevent CD40-mediated resistance to venetoclax. In contrast, inhibition of the electron transport chain (ETC) at complex I, III or V attenuated CLL activation and ATP production, and downregulated MCL-1 and BCL-XL, correlating with reduced CD40 surface expression. Moreover, ETC inhibition equaled mTOR1/2 but not mTOR1 inhibition alone for venetoclax resistance, and all three pathways were linked to control of general protein translation. In line with this, ETC plus mTOR inhibition synergistically counteracted venetoclax resistance. These findings link oxidative CLL metabolism to CD40 expression and cellular signaling, and may hold clinical potential.
CD40 信号通路上调慢性淋巴细胞白血病（CLL）淋巴结微环境中 BCL-XL 和 MCL-1 的表达，使 CLL 对 BCL-2 抑制剂 venetoclax 产生耐药性。在治疗环境中和经过长期实验室选择后，venetoclax 耐药性与代谢改变有关，但潜在机制尚不清楚。我们旨在通过 CD40 刺激作为肿瘤微环境介导的代谢变化的模型，发现其如何影响 venetoclax 的敏感性/耐药性。CD40 刺激增加了氧化磷酸化和糖酵解，但只有抑制氧化磷酸化才能对抗 venetoclax 耐药性。此外，阻断丙酮酸、谷氨酰胺或脂肪酸的线粒体输入会影响 CLL 的代谢，但不能防止 CD40 介导的 venetoclax 耐药性。相比之下，抑制电子传递链（ETC）复合物 I、III 或 V 会减弱 CLL 的激活和 ATP 产生，并下调 MCL-1 和 BCL-XL，与 CD40 表面表达减少相关。此外，ETC 抑制与 mTOR1/2 抑制等效，但与单独的 mTOR1 抑制不同，这三种途径都与控制一般蛋白质翻译有关。与此一致的是，ETC 加 mTOR 抑制协同对抗 venetoclax 耐药性。这些发现将氧化 CLL 代谢与 CD40 表达和细胞信号联系起来，可能具有临床潜力。
