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JMML is driven by germline <jats:italic>NF1<\/jats:italic> gene mutations, with additional somatic aberrations resulting in the <jats:italic>NF1<\/jats:italic> biallelic inactivation, leading to disease progression. Germline mutations in the <jats:italic>NF1<\/jats:italic> gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced <jats:italic>NF1<\/jats:italic> gene dose, immune cells are promoted in anti\u2010tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by <jats:italic>NF1<\/jats:italic> mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that <jats:italic>NF1<\/jats:italic> mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced <jats:italic>NF1<\/jats:italic> gene dose. <jats:italic>NF1<\/jats:italic> mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, <jats:italic>NF1<\/jats:italic>\u2010mutated iNKs had a high capacity to kill <jats:italic>NF1<\/jats:italic>\u2010KO iMacs. <jats:italic>NF1<\/jats:italic>\u2010mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline <jats:italic>NF1<\/jats:italic> mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.<\/jats:p>","DOI":"10.1111\/bjh.18851","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T11:04:40Z","timestamp":1683284680000},"page":"328-343","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Germline <i>Neurofibromin 1<\/i> mutation enhances the anti\u2010tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity"],"prefix":"10.1111","volume":"202","author":[{"given":"Wanqiao","family":"Wang","sequence":"first","affiliation":[{"name":"Pediatric Translational Medicine Institute, Department of Hematology &amp; Oncology Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Key Laboratory of Pediatric Hematology &amp; Oncology of China 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