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Patterns of hematopoietic lineage involvement in children with
neurofibromatosis type 1 and malignant myeloid disorders
DK Miles, MH Freedman, K Stephens, M Pallavicini, EL Sievers, M Weaver, T Grunberger, P Thompson and KM Shannon
Department of Pediatrics, University of California, San Francisco 94143-
0519, USA.
Children with neurofibromatosis type 1 (NF1) are at increased risk of
developing malignant myeloid disorders, particularly juvenile chronic
myelogenous leukemia/juvenile myelomonocytic leukemia (JCML/JMML). We
investigated bone marrows from 11 such patients (8 boys and 3 girls) and
detected allelic losses at the NF1 locus in 4 of them and probable losses
in 2 others. To determine which hematopoietic cell lineages were derived
from the abnormal clones, Epstein-Barr virus (EBV)-transformed cell lines
and CD34+ cells were analyzed from 3 children with JCML with allelic losses
in unfractionated marrow. CD34 cells from these 3 patients lacked the
normal NF1 allele, whereas EBV cell lines retained it. Erythroblasts
plucked from the burst-forming unit-erythroid colonies of one of these
children lacked the normal NF1 allele. We also studied a 10-month-old boy
with NF1 who developed an unusual myeloproliferative syndrome. His bone
marrow and EBV cell line both showed loss of the normal NF1 allele. In our
series and in the literature, male sex and maternal transmission of NF1
were associated with the highest risk of myeloid leukemia. These data (1)
provide strong genetic evidence that NF1 functions as a tumor-suppressor in
early myelopoiesis, (2) confirm the clonal nature of JCML/JMML, (3) suggest
that the elevation in fetal hemoglobin seen in JCML/JMML is a result of
primary involvement of erythroid progenitors in the malignant clone, (4)
show consistent loss of NF1 in the CD34 cells of affected children and show
that the malignant clone may also give rise to pre-B cells in some cases,
and (5) implicate epigenetic factors in the development of leukemia in
children with NF1.
Volume 88,
Issue 11,
pp. 4314-4320,
12/01/1996
Copyright © 1996 by The American Society of Hematology
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