Children with NF1 are at increased risk of myeloid leukemia, especially juvenile chronic myelogenous leukemia (JCML). We previously found loss of the normal NF1 allele in 5 of 11 affected children and here report 10 additional families who were investigated with 4 polymorphic markers within (3) or near (1) NF1, The bone marrows of 5 patients showed allelic loss at NF1. Four of these children had familial NF1 and the NF1 allele inherited from the unaffected parent was deleted in each case. We analyzed DNA prepared from Epstein-Barr virus (EBV) transformed cell lines and CD34+ cells from a number of children with allelic losses at NF1 and also studied erythroblasts plucked from BFU-E colonies in 1 patient. Normal NF1 alleles were lost in CD34+ cells from 3/3 cases and in BFU-E from the only patient studied. Normal NF1 alleles were retained in EBV lines from 3/4 patients and deleted in 1. The clinical picture of the 9 month old boy with EBV involvement was atypical for JCML but was reminiscent of Ph'-positive CML. However, a test for the Ph' chromosome was negative and he did not respond to hydroxyurea. We observed a skewed distribution among cases associated with familial NF1 with respect to both the sex of the transmitting parent and of the child with leukemia from our series and the literature as follows: mother with NF1, affected son (20 cases), father with NF1, affected son (8 cases); mother with NF1, affected daughter (4 cases); and, father with NF1, affected daughter (1 case). These data: (1) implicate NF1 as a tumor-suppressor in early myelopoiesis; (2) confirm the clonal nature of JCML; (3) demonstrate that transformation occurs in a cell committed to myeloid, but not B-lineage, differentiation in JCML; (4) indicate that loss of NF1 occurs at an earlier stage of hematopoietic development in some cases; and, (5) suggest that epigenetic factors play a role in the leukemia susceptibility seen in children with NF1.
|Original language||English (US)|
|Journal||Journal of Investigative Medicine|
|State||Published - Jan 1 1996|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)