Juvenile myelomonocytic leukemia in the context of neurofibromatosis type 1

Juvenile myelomonocytic leukemia (JMML) constitutes a rare hematological malignancy of the pediatric population, primarily occurring in patients younger than 4 years of age. Patients present with a variety of clinical findings, including leukocytosis with prominent monocytosis, as well as suppression of other hematopoietic lineages leading to anemia and thrombocytopenia. The World Health Organization recognized JMML as a myelodysplastic syndrome/myeloproliferative disorder, and criteria have been delineated for the diagnosis of JMML; among these criteria is the clinical diagnosis of neurofibromatosis type 1 (NF1), thus highlighting the importance of its association with JMML. Of note, about 10% of JMML patients also have NF1; the proposed mechanism for this association is underlying mutation of the NF1 gene on chromosome 17q, leading to increased RAS-pathway activity in germline-derived cells. Reports describe multiple mechanisms for NF1 loss of heterozygosity, especially segmental uniparental disomy of chromosome 17q. Additionally, juvenile xanthogranuloma (JXG) has been described to co-occur with JMML and NF1 and, in some cases, may be the first clue to a diagnosis of underlying JMML and NF1. Prognostic factors include a multitude of findings at diagnosis, as well as the presence of additional genetic or chromosomal aberrations. Definitive treatment for JMML is hematopoietic stem cell transplantation. However, targeted therapeutic approaches, primarily aimed at RAS pathway constituents, are under development. This chapter explores JMML as a distinct myelodysplastic syndrome/myeloproliferative disorder, with a focus on its association with NF1 and distinguishing features in this context.