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The Effects of Brown Fat Activation on Normal and Abnormal Hematopoiesis

CHENG Tianran^1,2, SHAO Ya^1,2, LIU Huan^1,2, ZHAO Hongfei^1,2, ZHAO Zihan^1,2, JIANG Shan³, ZHANG Shiyue^1,2, SUN Lu^1,2, WANG Tong^1,2, XU Yuanfu^1,2, CAO Yihai^4
*

( ¹ State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; ² Tianjin Institutes of Health Science, Tianjin 300020, China; ³ Clinical Laboratory, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; ⁴ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna1 17165, Sweden)

Abstract:

Activation of BAT (brown adipose tissue) can inhibit solid tumor growth, but its effect on normal or abnormal hematopoietic cells remains unclear. Therefore, in this study, the β3-adrenergic receptor agonist mirabegron was used to activate BAT in wild-type and leukemia mice, and the effects on normal hematopoietic cells and leukemia cells were observed and analyzed. The proportion of leukemia cells in bone marrow, spleen, liver, and peripheral blood of mice treated with mirabegron and control mice was analyzed at various time points. The proportion, number, cell cycle, apoptosis and colony formation ability of HS/PCs (hematopoietic stem/progenitor cells) and mature hematopoietic cells in the bone marrow of leukemia mice were analyzed. The activation degree of adipose tissue was verified. The role of BAT activation by mirabegron in leukemia was examined by surgical removal of BAT. The results showed that mirabegron treatment significantly activated BAT, reduced the proportion of leukemia cells in the bone marrow, spleen, liver and peripheral blood of acute leukemia mice, and prolonged the survival time. Mirabegron treatment had no significant effect on the proportion and number of mature immune cells and HS/PCs in the bone marrow of normal C57 mice, but in the leukemia mice, the proportion and absolute number of various mature immune cells in the bone marrow of the treatment group were significantly higher than those of the control group, the proportion and absolute number of HS/PCs in the bone marrow of the treatment group were significantly increased, the apoptosis of the cells was decreased, and the ability of colony formation was enhanced. Surgical removal of BAT blocked mirabegron-mediated anti-leukemic effects. Overall, these findings demonstrate that pretreatment with mirabegron can activate brown adipose tissue, suppress the proliferation of leukemia cells, enhance the proliferation, differentiation, and survival of normal hematopoietic stem/progenitor cells in leukemia mice, and extend the lifespan of mice. This offers a novel approach for future clinical management of leukemia.

CSTR: 32200.14.cjcb.2024.06.0003