MiR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20.

Zixing Liu,Ming Zhou,Kelly R Smith,Jingshan Huang,Ming Tan,Hung T Khong,Eun-Young Erin Ahn

doi:10.18632/oncotarget.12018

Zixing Liu, Ming Zhou + Show 5 more

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https://doi.org/10.18632/oncotarget.12018

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Abstract

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.

Highlights

In 2015, National Cancer Institute estimated there will be 54,270 new cases of leukemia (3.3% of all new cancer cases) and an estimated 24,450 people (4.1% of all cancer deaths) will die of this disease in the United States
We have reported that miR-125b plays an important role in cancer cell drug resistance and cancer stem cells enrichment [13,14]. miR-125b has been reported to inhibit cell differentiation [15,16,17,18]. miR-125b is highly expressed in hematopoietic stem cells, and promotes lymphoidfate decisions [19]
To determine whether miR-125b regulates the differentiation of T cells, Jurkat cells and a more differentiated cell line T2 cells were transfected with a control pMSCV-vetor and a miR125b expressing vector pMSCV-miR-125b (Figure 1B, Supplementary Figure 1) and the expression of CD4 were measured in these cells

Summary

Introduction

In 2015, National Cancer Institute estimated there will be 54,270 new cases of leukemia (3.3% of all new cancer cases) and an estimated 24,450 people (4.1% of all cancer deaths) will die of this disease in the United States. There are about 4,000 new cases of acute lymphoblastic leukemia in the United States each year [1]. T-ALL (T-cell acute lymphoblastic leukemia) is an aggressive hematopoietic cancer with a five year survival rate about 50% [2]. A significant number of T-ALL patients show poor responses to treatment. NOTCH1 and several microRNAs have been reported to play a key role in T cell differentiation and T-ALL development [2, 4,5]. The mechanisms of T-ALL development are still not fully understood

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