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journal article·2025-03Open access

CAMKIIδ Reinforces Lipid Metabolism and Promotes the Development of B Cell Lymphoma

Jiawei Zhang, Senlin Xu, Hui Fang, Dehao Wu, Ching Ouyang, Yunfei Shi, Zhenkang Hu, Mingfeng Zhang, Yaoyao Zhong, Junwei Zhao, Yichao Gan, Shize Zhang, Xiaoqian Liu, Jie Yin, Yuan Li, Mengyue Tang, Yingda Wang, Ling Li, Wing C Chan, David Horne, Mingye Feng, Wendong Huang, Ying Gu

Advanced Science· Volume 12· Issue 10
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Abstract

Abstract The most prevalent types of lymphomas are B cell lymphomas (BCL). Newer therapies for BCL have improved the prognosis for many patients. However, approximately 30% with aggressive BCL either remain refractory or ultimately relapse. These patients urgently need other options. This study shows how calcium/calmodulin‐dependent protein kinase II delta (CAMKIIδ) is pivotal for BCL development. In BCL cells, ablation of CAMKIIδ inhibits both lipolysis from lipid droplets and oxidative phosphorylation (OXPHOS). With lipolysis blocked, BCL progression is markedly suppressed in two distinct BCL mouse models: MYC‐driven EµMyc mice and Myc/Bcl2 double‐expressed mice. When CAMKIIδ is present, it destabilizes transcription factor Forkhead Box O3A (FOXO3A) by phosphorylating it at Ser7 and Ser12. This then permits transcription of downstream gene IRF4 – a master transcription factor of lipid metabolism. The CAMKIIδ/FOXO3A axis bolsters lipid metabolism, mitochondrial respiration, and tumor fitness in BCL under metabolic stress. This study also evaluates Tetrandrine (TET), a small molecule compound, as a potent CAMKIIδ inhibitor. TET attenuates metabolic fitness and elicits therapeutic responses both in vitro and in vivo. Collectively, this study highlights how CAMKIIδ is critical in BCL progression. The results also pave the way for innovative therapeutic strategies for treating aggressive BCL.
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Research context

Ceramics & glassesComposites

OpenAlex topics: FOXO transcription factor regulation · Pancreatic function and diabetes · Endoplasmic Reticulum Stress and Disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Cancer Institute (Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education) Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 China

Molecular and Cellular Biology of Cancer Program & Department of Diabetes Complications and Metabolism Arthur Riggs Diabetes & Metabolism Research Institute Beckman Research Institute City of Hope Duarte CA 91010 USA

Center for Genetic Medicine, the Fourth Affiliated Hospital School of Medicine Zhejiang University Yiwu 322000 China

Institute of Genetics International School of Medicine Zhejiang University Hangzhou 310058 China

Department of Digestive Fuzhou University Affiliated Provincial Hospital Fuzhou Fujian 350001 China

Integrative Genomic Core City of Hope National Medical Center Duarte CA 91010 USA

Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Department of Pathology Peking University Cancer Hospital and Institute Beijing 100142 China

Department of Hematology The Affiliated Yantai Yuhuangding Hospital of Qingdao University Yantai Shandong 264000 China

Irell and Manella Graduate School of Biological Sciences Beckman Research Institute City of Hope Duarte CA 91010 USA

Department of Hematologic Malignancies Translational Science Beckman Research Institute City of Hope National Medical Center Duarte CA 91010 USA

Department of Pathology City of Hope National Medical Center Duarte CA 91010 USA

Department of Molecular Medicine Beckman Research Institute City of Hope National Medical Center Duarte CA 91010 USA

Department of Immuno‐oncology Beckman Research Institute City of Hope National Medical Center Duarte CA 91010 USA

Zhejiang Provincial Key Lab of Genetic and Developmental Disorder Hangzhou 310058 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Zhejiang Province · National Institutes of Health

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