Journal
JOURNAL OF EXTRACELLULAR VESICLES
Volume 10, Issue 13, Pages -Publisher
WILEY
DOI: 10.1002/jev2.12168
Keywords
AML; CD8+ T cells; creatine; extracellular vesicles; nucleophosmin
Categories
Funding
- National Natural Science Foundation of China [NSFC82072353]
- outstanding Postgraduate Fund of Chongqing Medical University [BJRC202009]
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In patients with NPM1-mutated AML, leukemic cells release miR-19a-3p through sEVs to suppress the immune function of CD8+ T cells by inhibiting creatine import mediated by SLC6A8. This immune evasion mechanism may serve as a promising therapeutic target for NPM1-mutated AML.
Acute myeloid leukaemia (AML) carrying nucleophosmin (NPM1) mutations has been defined as a distinct entity of acute leukaemia. Despite remarkable improvements in diagnosis and treatment, the long-term outcomes for this entity remain unsatisfactory. Emerging evidence suggests that leukaemia, similar to other malignant diseases, employs various mechanisms to evade killing by immune cells. However, the mechanism of immune escape in NPM1-mutated AML remains unknown. In this study, both serum and leukemic cells from patients with NPM1-mutated AML impaired the immune function of CD8+ T cells in a co-culture system. Mechanistically, leukemic cells secreted miR-19a-3p into the tumour microenvironment (TME) via small extracellular vesicles (sEVs), which was controlled by the NPM1-mutated protein/CCCTC-binding factor (CTCF)/poly (A)-binding protein cytoplasmic 1 (PABPC1) signalling axis. sEV-related miR-19a-3p was internalized by CD8+ T cells and directly repressed the expression of solute-carrier family 6 member 8 (SLC6A8; a creatine-specific transporter) to inhibit creatine import. Decreased creatine levels can reduce ATP production and impair CD8+ T cell immune function, leading to immune escape by leukemic cells. In summary, leukemic cell-derived sEV-related miR-19a-3p confers immunosuppression to CD8+ T cells by targeting SLC6A8-mediated creatine import, indicating that sEV-related miR-19a-3p might be a promising therapeutic target for NPM1-mutated AML.
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