miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20.
miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20.
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DOI：
10.18632/oncotarget.12018
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Tan M
中科院分区：
文献类型：
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作者：
Liu Z;Smith KR;Khong HT;Huang J;Ahn EE;Zhou M;Tan M
T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性造血系统恶性肿瘤。尽管有报道称miR-125b的过度表达会导致T-ALL的发生，但miR-125b作用的潜在机制仍不清楚。本研究的目的是阐明 miR-125b 在 T-ALL 发展中的作用。我们发现miR-125b在未分化白血病T细胞（CD4阴性）中高表达，而在分化T细胞（CD4阳性）中低表达。 miR-125b 的过表达增加了 T 细胞中的 CD4 阴性细胞群，而 miR-125b-sponge 耗尽 miR-125b 则减少了 CD4 阴性细胞群。我们发现 A20 (TNFAIP3) 是 T 细胞中 miR-125b 的直接靶标。 miR-125b 的过表达还通过靶向 A20 增加了 T 细胞的葡萄糖摄取和耗氧量。此外，miR-125b过表达细胞中A20的恢复减少了T细胞白血病中的CD4阴性群体，并将葡萄糖摄取和耗氧量降低至载体转染的T细胞的基础水平。总之，我们的数据表明 miR-125b 通过靶向 A20 调节 T 细胞葡萄糖代谢的分化和重编程。由于去分化和葡萄糖代谢失调都会导致 T 细胞白血病的发生，因此这些发现为 T-ALL 的理解和治疗提供了新的见解。
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy. Although it has been reported that overexpression of miR-125b leads to T-ALL development, the underlying mechanisms of miR-125b action are still unclear. The goal of this study is to delineate the role of miR-125b in T-ALL development. We found that miR-125b is highly expressed in undifferentiated leukemic T cells (CD4-negative) while its expression is low in differentiated T cells (CD4-positive). Overexpression of miR-125b increased the CD4-negative population in T cells, whereas depletion of miR-125b by miR-125b-sponge decreased the CD4-negative cell population. We identified that A20 (TNFAIP3) is a direct target of miR-125b in T cells. Overexpression of miR-125b also increased glucose uptake and oxygen consumption in T cells through targeting A20. Furthermore, restoration of A20 in miR-125b-overexpressing cells decreased the CD4-negative population in T cell leukemia, and decreased glucose uptake and oxygen consumption to the basal level of T cells transfected with vector. In conclusion, our data demonstrate that miR-125b regulates differentiation and reprogramming of T cell glucose metabolism via targeting A20. Since both de-differentiation and dysregulated glucose metabolism contribute to the development of T-cell leukemia, these findings provide novel insights into the understanding and treatment of T-ALL.