Biallelic inactivation of the NF1 tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup

Summary Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF‐1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild‐type allele. Here we examined the two‐hit concept in leukaemic cells of 25 patients with JMML and NF‐1. Ten patients with JMML/NF‐1 exhibited a NF1 loss‐of‐function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound‐heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF‐1 and no variation in the JMML‐associated driver genes PTPN11, KRAS, NRAS or CBL (JMML‐5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound‐heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF‐1 reliably indicates a NF1‐driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF‐1. Children with neurofibromatosis type 1 (NF‐1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild‐type allele. We examined the two‐hit concept in leukaemic cells of 25 patients with JMML and clinical diagnosis of NF‐1 and confirmed biallelic NF1 inactivation in all cases but one. Among 16 JMML patients without clinical signs of NF‐1 and no variation in other JMML‐associated driver genes, eight patients exhibited NF1‐inactivating variants (six biallelic, two monoallelic). The data show that the clinical diagnosis of JMML/NF‐1 reliably indicates a NF1‐driven JMML subtype, and that NF1 genetic analysis should be included in the diagnostic workup of JMML even in the absence of clinical evidence of NF‐1.