MUTATIONS OF THE NF1 GENE IN CHILDREN WITH JUVENILE MYELOMONOCYTIC LEUKEMIA WITHOUT CLINICAL-EVIDENCE OF NEUROFIBROMATOSIS, TYPE-1

Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphat e hydrolysis on Ras proteins, The purpose of this study was to determi ne if the NF1 gene was involved in the pathogenesis of JMML in childre n without a clinical diagnosis of NF1. An in vitro transcription and t ranslation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single stranded c onformational polymorphism analysis was used to detect RAS point mutat ions in these samples. We confirmed mutations of NF1 in three leukemia s, one of which also showed loss of the normal NF1 allele. An NF1 muta tion was detected in normal tissue from the only patient tested and th is suggests that JMML may be the presenting feature of NF1 in some chi ldren, Activating RAS mutations were found in four patients; as expect ed, none of these samples harbored NF1 mutations. Because 10% to 14% o f children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases. (C) 1998 by The American Society of Hematology.