Myeloid malignancies induced by alkylating agents in Nf1 mice

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML and MDS) are severe late complications of treatment with genotoxic chemothe rapeutic agents. Children with neurofibromatosis type 1 (NF1) are predispos ed to malignant myeloid disorders that are associated with inactivation of the NF7 tumor suppressor gene in the leukemic clone. Recent clinical data s uggest that NF1 might be also associated with an increased risk of t-AML af ter treatment with alkyating agents. To test this hypothesis, we administer ed cyclophosphamide or etoposide to cohorts of wild-type and heterozygous N f1 knockout mice. Cyclophosphamide exposure cooperated strongly with hetero zygous inactivation of Nf1 in myeloid leukemogenesis, while etoposide did n ot. Somatic loss of the normal Nf1 allele correlated with clinical disease and was more common in 129/Sv mice than in 129/Sv x C57BL/6 animals. Leukem ic cells showing loss of heterozygosity at Nf1 retained a structural allele on each chromosome 11 homolog, These studies establish a novel in vivo mod el of alkylator-induced myeloid malignancy that will facilitate mechanistic and translational studies. (C) 1999 by The American Society of Hematology.