Niemeyer et al. reported that 11% of the JMML patients have clinical signs of neurofibromatosis type 1. 5 Thereafter, Side et al. found NF1 gene mutations in 15% of the JMML patients without clinical signs of NF1 (Figure 2). 10 The NF1 gene is a tumor suppressor gene encoding for neurofibromin, and is a GTPase activating protein hydrolysing GTP-RAS into GDP-RAS. 10 JMML cells from children with NF1 showed a reduced neurofibromin activity, resulting in elevated GTP-RAS expression. 11 In 2007, Flotho et al. described somatic loss of heterozygosity (LOH) in 4 out of 5 JMML cases with NF1. In the leukemic cells the wild-type NF1 gene was replaced by a second copy of the NF1 mutant 17q arm, resulting from uniparental disomy. 12 In the current issue of this journal, Steinemann et al. 13 describe bi-allelic NF1 gene inactivation in all cases in a larger cohort of JMML patients with NF1. Again, this was either caused by LOH (n= 10), or by somatic mutations of the NF1 gene (n= 5). This indicates that although NF1 predisposes for JMML and other leukemias, second events are necessary to abolish the complete function of the NF1 gene in the development of malignancies. Recently, comparable bi-allelic mutations in the NF1 gene were also found in non-syndromic AML and T-ALL patients, which underscores the fact that bi-allelic inactivation of the NF1 gene is an important mechanism in hematologic malignancies, but also that it is not JMML-specific. 14