Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras.
Children with neurofibromatosis, type 1 (NF-1) are at increased risk of developing malignant myeloid disorders and their bone marrows frequently show loss of the normal allele of the NF1 tumor-suppressor gene. NF1 encodes a protein called neurofibromin, which accelerates guanosine triphosphate (GTP) hydrolysis on the p21ras (Ras) family of signaling proteins. We used a genetic approach to test the hypothesis that NF1 negatively regulates myeloid cell growth through its effect on Ras. This model predicts that, if RAS mutations and loss of NF1 function deregulate myeloid growth by the same biomechanical mechanism, then activating RAS mutations will be restricted to children with malignant myeloid disorders who do not have NF-1. We studied 71 children, including 28 with bone marrow monosomy 7 syndrome (Mo7), 35with juvenile chronic myelogenous leukemia (JCML), three with other forms of preleukemia, and five with acute myelogenous leukemia (AML), for activating mutations 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 mutations 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). These data from primary human cancer cells provide strong genetic evidence that NF1 limits the growth of myeloid cells by regulating Ras.
Kalra
R
R
Department of Pediatrics, University of California, San Francisco.
Paderanga
D C
DC
Olson
K
K
Shannon
K M
KM
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D005091:Exons; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008969:Molecular Sequence Data; D025542:Neurofibromin 1; D009838:Oligodeoxyribonucleotides; D017354:Point Mutation; D011289:Preleukemia / Q000235:genetics*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000378:metabolism*; D015183:Restriction Mapping; D015398:Signal Transduction
D003062:Codon; D025542:Neurofibromin 1; D009838:Oligodeoxyribonucleotides; D011506:Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)