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Genetic analysis is consistent with the hypothesis that NF1 limits myeloid
cell growth through p21ras
R Kalra, DC Paderanga, K Olson and KM Shannon
Department of Pediatrics, University of California, San Francisco.
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.
Volume 84,
Issue 10,
pp. 3435-3439,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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