PATTERNS OF HEMATOPOIETIC LINEAGE INVOLVEMENT IN CHILDREN WITH NEUROFIBROMATOSIS TYPE-1 AND MALIGNANT MYELOID DISORDERS

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) a nd detected allelic losses at the NF1 locus in 4 of them and probable losses in 2 others. To determine which hematopoietic cell lineages wer e derived from the abnormal clones, Epstein-Barr virus (EBV)-transform ed cell lines and CD34(+) cells were analyzed from 3 children with JCM L with allelic losses in unfractionated marrow. CD34 cells from these 3 patients lacked the normal NF1 allele, whereas EBV cell lines retain ed it. Erythroblasts plucked from the burst-forming unit-erythroid col onies of one of these children lacked the normal NF1 allele. We also s tudied a 10-month-old boy with NF1 who developed an unusual myeloproli ferative syndrome. His bone marrow and EBV cell line both showed loss of the normal NF1 allele, In our series and in the literature, male se x and maternal transmission of NF1 were associated with the highest ri sk of myeloid leukemia. These data (1) provide strong genetic evidence that NF1 functions as a tumor-suppressor in early myelopoiesis, (2) c onfirm the clonal nature of JCML/JMML, (3) suggest that the elevation in fetal hemoglobin seen in JCML/JMML is a result of primary involveme nt of erythroid progenitors in the malignant clone, (4) show consisten t 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 chi ldren with NF1. (C) 1996 by The American Society of Hematology.