MilliporeSigma
  • Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity.

Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity.

British journal of haematology (2023-05-05)
Wanqiao Wang, Xin Li, Xia Qin, Yan Miao, Yingwen Zhang, Shanshan Li, Ruen Yao, Yi Yang, Lisha Yu, Hua Zhu, Lili Song, Shengqiao Mao, Xiumin Wang, Jing Chen, Haizhong Feng, Yanxin Li
ABSTRACT

Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 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 NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-OCT-4 [POU5F1] Antibody, clone 7F9.2, Alexa Fluor 488 conjugate, clone 7F9.2, from mouse, ALEXA FLUOR 488
Sigma-Aldrich
Sodium selenite, BioReagent, suitable for cell culture, ≥98%
Sigma-Aldrich
Anti-TRA-1-60 Antibody, clone TRA-1-60, clone TRA-1-60, Chemicon®, from mouse