Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia
Abstract Background Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathwa...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2016-03-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13045-016-0256-3 |
| _version_ | 1831841675524177920 |
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| author | Yozo Nakazawa Kazuyuki Matsuda Takashi Kurata Akane Sueki Miyuki Tanaka Kazuo Sakashita Chihaya Imai Matthew H. Wilson Kenichi Koike |
| author_facet | Yozo Nakazawa Kazuyuki Matsuda Takashi Kurata Akane Sueki Miyuki Tanaka Kazuo Sakashita Chihaya Imai Matthew H. Wilson Kenichi Koike |
| author_sort | Yozo Nakazawa |
| collection | DOAJ |
| description | Abstract Background Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML. Methods We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34+ cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34+ cells. Results GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34+ cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34+ cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34+ cell proliferation, particularly CD34+CD38− cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34+ cell colony growth. Conclusions Ligand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML. |
| first_indexed | 2024-12-23T06:32:59Z |
| format | Article |
| id | doaj.art-222a85f019e440759c4c2618eadb512b |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-23T06:32:59Z |
| publishDate | 2016-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-222a85f019e440759c4c2618eadb512b2022-12-21T17:56:52ZengBMCJournal of Hematology & Oncology1756-87222016-03-019111110.1186/s13045-016-0256-3Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemiaYozo Nakazawa0Kazuyuki Matsuda1Takashi Kurata2Akane Sueki3Miyuki Tanaka4Kazuo Sakashita5Chihaya Imai6Matthew H. Wilson7Kenichi Koike8Department of Pediatrics, Shinshu University School of MedicineDepartment of Laboratory Medicine, Shinshu University HospitalDepartment of Pediatrics, Shinshu University School of MedicineDepartment of Laboratory Medicine, Shinshu University HospitalDepartment of Pediatrics, Shinshu University School of MedicineDepartment of Pediatrics, Shinshu University School of MedicineDepartment of Pediatrics, Niigata University School of MedicineDepartment of Medicine, Division of Nephrology and Hypertension, Vanderbilt University School of MedicineDepartment of Pediatrics, Shinshu University School of MedicineAbstract Background Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML. Methods We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34+ cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34+ cells. Results GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34+ cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34+ cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34+ cell proliferation, particularly CD34+CD38− cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34+ cell colony growth. Conclusions Ligand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML.http://link.springer.com/article/10.1186/s13045-016-0256-3Juvenile myelomonocytic leukemiaChimeric antigen receptorGM-CSF receptorLeukemic stem cellspiggyBac transposon |
| spellingShingle | Yozo Nakazawa Kazuyuki Matsuda Takashi Kurata Akane Sueki Miyuki Tanaka Kazuo Sakashita Chihaya Imai Matthew H. Wilson Kenichi Koike Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia Journal of Hematology & Oncology Juvenile myelomonocytic leukemia Chimeric antigen receptor GM-CSF receptor Leukemic stem cells piggyBac transposon |
| title | Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia |
| title_full | Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia |
| title_fullStr | Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia |
| title_full_unstemmed | Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia |
| title_short | Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia |
| title_sort | anti proliferative effects of t cells expressing a ligand based chimeric antigen receptor against cd116 on cd34 cells of juvenile myelomonocytic leukemia |
| topic | Juvenile myelomonocytic leukemia Chimeric antigen receptor GM-CSF receptor Leukemic stem cells piggyBac transposon |
| url | http://link.springer.com/article/10.1186/s13045-016-0256-3 |
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