GENETIC-ANALYSIS IS CONSISTENT WITH THE HYPOTHESIS THAT NF1 LIMITS MYELOID CELL-GROWTH THROUGH P21(RAS)

Children with neurofibromatosis, type 1 (NF-1) are at increased risk o f developing malignant myeloid disorders and their bone marrows freque ntly show loss of the normal allele of the NF1 tumor-suppressor gene. NF1 encodes a protein called neurofibromin, which accelerates guanosin e triphosphate (GTP) hydrolysis on the p21(ras) (Ras) family of signal ing proteins. We used a genetic approach to test the hypothesis that N F1 negatively regulates myeloid cell growth through its effect on Ras. This model predicts that, if RAS mutations and loss of NF1 function d eregulate myeloid growth by the same biomechanical mechanism, then act ivating RAS mutations will be restricted to children with malignant my eloid disorders who do not have NF-1. We studied 71 children, includin g 28 with bone marrow monosomy 7 syndrome (Mo7), 35with juvenile chron ic myelogenous leukemia (JCML), three with other forms of preleukemia, and five with acute myelogenous leukemia (AML), for activating mutati ons of KRAS and NRAS. The incidence of RAS mutations was 21% (12 of 55 ) in patients without NF-1 and 0% (zero of 16) in children with NF-1 ( P = .04). Among the 55 patients who did not have NF-1, we found RAS mu tations in four of 27 with Mo 7, in five of 24 with JCML, in two of 3 with AML, and in a patient with myeloproliferative syndrome (MPS). The se data from primary human cancer cells provide strong genetic evidenc e that NF1 limits the growth of myeloid cells by regulating Ras. (C) 1 994 by The American Society of Hematology.