Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia
Abstract Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59040-6 |
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| author | Juwita Werner Alex G. Lee Chujing Zhang Sydney Abelson Sherin Xirenayi Jose Rivera Khadija Yousuf Hanna Shin Bonell Patiño-Escobar Stefanie Bachl Kamal Mandal Abhilash Barpanda Emilio Ramos Adila Izgutdina Sibapriya Chaudhuri William C. Temple Shubhmita Bhatnagar Jackson K. Dardis Julia Meyer Carolina Morales Soheil Meshinchi Mignon L. Loh Benjamin Braun Sarah K. Tasian Arun P. Wiita Elliot Stieglitz |
| author_facet | Juwita Werner Alex G. Lee Chujing Zhang Sydney Abelson Sherin Xirenayi Jose Rivera Khadija Yousuf Hanna Shin Bonell Patiño-Escobar Stefanie Bachl Kamal Mandal Abhilash Barpanda Emilio Ramos Adila Izgutdina Sibapriya Chaudhuri William C. Temple Shubhmita Bhatnagar Jackson K. Dardis Julia Meyer Carolina Morales Soheil Meshinchi Mignon L. Loh Benjamin Braun Sarah K. Tasian Arun P. Wiita Elliot Stieglitz |
| author_sort | Juwita Werner |
| collection | DOAJ |
| description | Abstract Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive immunotherapy with chimeric antigen receptor (CAR) T cells has improved outcomes for patients with advanced lymphoid malignancies, it has not been comprehensively evaluated in JMML. In the present study, we use bulk and single-cell RNA sequencing, mass spectrometry, and flow cytometry to identify overexpression of CLL-1 (encoded by CLEC12A) on the cell surface of cells from patients with JMML. We develop immunotherapy with CLL-1 CAR T cells (CLL1CART) for preclinical testing and report in vitro and in vivo anti-leukemia activity. Notably, CLL1CART reduce the number of leukemic stem cells and serial transplantability in vivo. These preclinical data support the development and clinical investigation of CLL-1-targeting immunotherapy in children with relapsed/refractory JMML. |
| format | Article |
| id | doaj-art-458e1fbae046420a84b88b1ef710a8d9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-458e1fbae046420a84b88b1ef710a8d92025-08-20T03:53:32ZengNature PortfolioNature Communications2041-17232025-04-0116112010.1038/s41467-025-59040-6Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemiaJuwita Werner0Alex G. Lee1Chujing Zhang2Sydney Abelson3Sherin Xirenayi4Jose Rivera5Khadija Yousuf6Hanna Shin7Bonell Patiño-Escobar8Stefanie Bachl9Kamal Mandal10Abhilash Barpanda11Emilio Ramos12Adila Izgutdina13Sibapriya Chaudhuri14William C. Temple15Shubhmita Bhatnagar16Jackson K. Dardis17Julia Meyer18Carolina Morales19Soheil Meshinchi20Mignon L. Loh21Benjamin Braun22Sarah K. Tasian23Arun P. Wiita24Elliot Stieglitz25Department of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Laboratory Medicine, University of CaliforniaDepartment of Medicine, University of CaliforniaDepartment of Laboratory Medicine, University of CaliforniaDepartment of Laboratory Medicine, University of CaliforniaDepartment of Laboratory Medicine, University of CaliforniaDepartment of Laboratory Medicine, University of CaliforniaDivision of Hematology/Oncology, Department of Medicine, University of CaliforniaDivision of Pediatric Allergy, Immunology, and Bone Marrow Transplant, University of CaliforniaDivision of Oncology and Center for Childhood Cancer Research, Children’s Hospital of PhiladelphiaDivision of Oncology and Center for Childhood Cancer Research, Children’s Hospital of PhiladelphiaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaClinical Research Division, Department of Pediatrics, Fred Hutchinson Cancer CenterSeattle Children’s Hospital, The Ben Towne Center for Childhood Cancer Research, University of WashingtonDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaDivision of Oncology and Center for Childhood Cancer Research, Children’s Hospital of PhiladelphiaDepartment of Laboratory Medicine, University of CaliforniaDepartment of Pediatrics, Benioff Children’s Hospitals, University of CaliforniaAbstract Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive immunotherapy with chimeric antigen receptor (CAR) T cells has improved outcomes for patients with advanced lymphoid malignancies, it has not been comprehensively evaluated in JMML. In the present study, we use bulk and single-cell RNA sequencing, mass spectrometry, and flow cytometry to identify overexpression of CLL-1 (encoded by CLEC12A) on the cell surface of cells from patients with JMML. We develop immunotherapy with CLL-1 CAR T cells (CLL1CART) for preclinical testing and report in vitro and in vivo anti-leukemia activity. Notably, CLL1CART reduce the number of leukemic stem cells and serial transplantability in vivo. These preclinical data support the development and clinical investigation of CLL-1-targeting immunotherapy in children with relapsed/refractory JMML.https://doi.org/10.1038/s41467-025-59040-6 |
| spellingShingle | Juwita Werner Alex G. Lee Chujing Zhang Sydney Abelson Sherin Xirenayi Jose Rivera Khadija Yousuf Hanna Shin Bonell Patiño-Escobar Stefanie Bachl Kamal Mandal Abhilash Barpanda Emilio Ramos Adila Izgutdina Sibapriya Chaudhuri William C. Temple Shubhmita Bhatnagar Jackson K. Dardis Julia Meyer Carolina Morales Soheil Meshinchi Mignon L. Loh Benjamin Braun Sarah K. Tasian Arun P. Wiita Elliot Stieglitz Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia Nature Communications |
| title | Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia |
| title_full | Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia |
| title_fullStr | Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia |
| title_full_unstemmed | Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia |
| title_short | Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia |
| title_sort | cellular immunotherapy targeting cll 1 for juvenile myelomonocytic leukemia |
| url | https://doi.org/10.1038/s41467-025-59040-6 |
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