biostudies-literatureWerner JNCI NIH HHS3804https://www.ebi.ac.uk/biostudies/studies/S-EPMC12019388biostudies-literatureUnknown16(1)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.Nature communicationsCellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia.PMC12019388U54 CA196519R37 CA266550P30 CA082103R50 CA274213Tasian SKLoh MLBarpanda AMorales CXirenayi SPatino-Escobar BTemple WCShin HStieglitz EChaudhuri SMandal KWiita APZhang CBraun BYousuf KBachl SWerner JAbelson SMeshinchi SMeyer JDardis JKRivera JBhatnagar SIzgutdina ALee AGRamos EfalseCellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia.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.2025-01-01T00:00:00Z2025 Apr2026-06-02T19:06:02.158Z2026-04-19T03:14:02.238ZS-EPMC120193884026892710.1038/s41467-025-59040-6