Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-11-01
|
| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.12168 |
| _version_ | 1830343538358878208 |
|---|---|
| author | Meixi Peng Jun Ren Yipei Jing Xueke Jiang Qiaoling Xiao Junpeng Huang Yonghong Tao Li Lei Xin Wang Zailin Yang Zesong Yang Qian Zhan Can Lin Guoxiang Jin Xian Zhang Ling Zhang |
| author_facet | Meixi Peng Jun Ren Yipei Jing Xueke Jiang Qiaoling Xiao Junpeng Huang Yonghong Tao Li Lei Xin Wang Zailin Yang Zesong Yang Qian Zhan Can Lin Guoxiang Jin Xian Zhang Ling Zhang |
| author_sort | Meixi Peng |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T22:10:02Z |
| format | Article |
| id | doaj.art-cb84c96563384f6794e5ae30574aab8d |
| institution | Directory Open Access Journal |
| issn | 2001-3078 |
| language | English |
| last_indexed | 2024-12-19T22:10:02Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj.art-cb84c96563384f6794e5ae30574aab8d2022-12-21T20:03:56ZengWileyJournal of Extracellular Vesicles2001-30782021-11-011013n/an/a10.1002/jev2.12168Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemiaMeixi Peng0Jun Ren1Yipei Jing2Xueke Jiang3Qiaoling Xiao4Junpeng Huang5Yonghong Tao6Li Lei7Xin Wang8Zailin Yang9Zesong Yang10Qian Zhan11Can Lin12Guoxiang Jin13Xian Zhang14Ling Zhang15Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaDepartment of Hematology The First Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Clinical Laboratory The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Hematology The First Affiliated Hospital of Chongqing Medical University Chongqing ChinaThe Center for Clinical Molecular Medical detection The First Affiliated Hospital of Chongqing Medical University Chongqing ChinaKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaGuangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou ChinaImmunology Program Memorial Sloan Kettering Cancer Center New York New York USAKey Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education School of Laboratory Medicine Chongqing Medical University Chongqing ChinaAbstract 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.https://doi.org/10.1002/jev2.12168AMLCD8+ T cellscreatineextracellular vesiclesnucleophosmin |
| spellingShingle | Meixi Peng Jun Ren Yipei Jing Xueke Jiang Qiaoling Xiao Junpeng Huang Yonghong Tao Li Lei Xin Wang Zailin Yang Zesong Yang Qian Zhan Can Lin Guoxiang Jin Xian Zhang Ling Zhang Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia Journal of Extracellular Vesicles AML CD8+ T cells creatine extracellular vesicles nucleophosmin |
| title | Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_full | Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_fullStr | Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_full_unstemmed | Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_short | Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_sort | tumour derived small extracellular vesicles suppress cd8 t cell immune function by inhibiting slc6a8 mediated creatine import in npm1 mutated acute myeloid leukaemia |
| topic | AML CD8+ T cells creatine extracellular vesicles nucleophosmin |
| url | https://doi.org/10.1002/jev2.12168 |
| work_keys_str_mv | AT meixipeng tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT junren tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT yipeijing tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT xuekejiang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT qiaolingxiao tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT junpenghuang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT yonghongtao tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT lilei tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT xinwang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT zailinyang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT zesongyang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT qianzhan tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT canlin tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT guoxiangjin tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT xianzhang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia AT lingzhang tumourderivedsmallextracellularvesiclessuppresscd8tcellimmunefunctionbyinhibitingslc6a8mediatedcreatineimportinnpm1mutatedacutemyeloidleukaemia |