Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA.
Department of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA.
Cell Mol Biol Lett. 2023 May 24;28(1):45. doi: 10.1186/s11658-023-00455-8.
CD36 has been identified as a potential therapeutic target both in leukemic cells and in the tumor immune microenvironment. In acute myeloid leukemia (AML), we found that APOC2 acts with CD36 to promote leukemia growth by activating the LYN-ERK signaling. CD36 also plays a role in lipid metabolism of cancer associated T-cells leading to impaired cytotoxic CD8 T-cell and enhanced T cell function. To establish CD36 as a viable therapeutic target in AML, we investigated whether targeting CD36 has any detrimental impact on normal hematopoietic cells.
Differential expression data of CD36 during human and mouse normal hematopoiesis were examined and compared. Cd36 knockout (Cd36-KO) mice were evaluated for blood analysis, hematopoietic stem cells and progenitors (HSPCs) function and phenotype analyses, and T cells in vitro expansion and phenotypes in comparison with wild type (WT) mice. In addition, MLL-PTD/FLT3-ITD leukemic cells were engrafted into Cd36-KO and WT mice, and leukemia burden was compared between groups.
RNA-Seq data showed that Cd36 expression was low in HSPCs and increased as cells matured. Phenotypic analysis revealed limited changes in blood count except for a slight yet significantly lower red blood cell count and hemoglobin and hematocrit levels in Cd36-KO mice compared with WT mice (P < 0.05). In vitro cell proliferation assays of splenocytes and HSPCs from Cd36-KO mice showed a similar pattern of expansion to that of cells from WT mice. Characterization of HSPCs showed similar percentages of the different progenitor cell populations between Cd36-KO with WT mice. However, Cd36-KO mice exhibited ~ 40% reduction of the number of colonies developed from HSPCs cells compared with WT mice (P < 0.001). Cd36-KO and WT mice presented comparably healthy BM transplant in non-competitive models and developed similar leukemia burden.
Although the loss of Cd36 affects the hematopoietic stem cell and erythropoiesis, limited detrimental overall impact was observed on normal Hematopoietic and leukemic microenvironments. Altogether, considering the limited impact on normal hematopoiesis, therapeutic approaches to target CD36 in cancer are unlikely to result in toxicity to normal blood cells.
CD36 已被确定为白血病细胞和肿瘤免疫微环境中的潜在治疗靶点。在急性髓系白血病 (AML) 中，我们发现 APOC2 与 CD36 一起通过激活 LYN-ERK 信号促进白血病的生长。CD36 还在与癌症相关的 T 细胞的脂质代谢中发挥作用，导致细胞毒性 CD8 T 细胞受损和 T 细胞功能增强。为了将 CD36 确立为 AML 的可行治疗靶点，我们研究了靶向 CD36 是否对正常造血细胞有任何不利影响。
研究了人类和小鼠正常造血过程中 CD36 的差异表达数据，并进行了比较。评估了 Cd36 敲除 (Cd36-KO) 小鼠的血液分析、造血干细胞和祖细胞 (HSPCs) 功能和表型分析，以及与野生型 (WT) 小鼠相比的 T 细胞体外扩增和表型。此外，将 MLL-PTD/FLT3-ITD 白血病细胞植入 Cd36-KO 和 WT 小鼠体内，并比较两组之间的白血病负担。
RNA-Seq 数据显示，CD36 在 HSPCs 中的表达较低，随着细胞成熟而增加。表型分析显示，除了 Cd36-KO 小鼠的红细胞计数、血红蛋白和血细胞比容略低且具有显著差异 (P<0.05) 外，血液计数的变化有限。Cd36-KO 小鼠脾细胞和 HSPCs 的体外细胞增殖试验显示出与 WT 小鼠相似的扩增模式。HSPCs 的特征分析显示，Cd36-KO 小鼠与 WT 小鼠的不同祖细胞群体百分比相似。然而，与 WT 小鼠相比，Cd36-KO 小鼠的 HSPC 细胞形成的集落数量减少了约 40% (P<0.001)。Cd36-KO 和 WT 小鼠在非竞争性模型中表现出相似的 BM 移植健康状况，并发展出相似的白血病负担。
尽管 CD36 的缺失会影响造血干细胞和红细胞生成，但对正常造血和白血病微环境的总体影响有限。总的来说，考虑到对正常造血的影响有限，针对癌症中 CD36 的治疗方法不太可能导致对正常血细胞的毒性。
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