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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3617-3623
RAPID COMMUNICATION
Myeloid Malignancies Induced by Alkylating Agents in Nf1 Mice
Nidal Mahgoub,
Brigit R. Taylor,
Michelle M. Le Beau,
Mary Gratiot,
Katrin M. Carlson,
Susan K. Atwater,
Tyler Jacks, and
Kevin M. Shannon
From the Departments of Pediatrics and Laboratory Medicine,
University of California, San Francisco, CA; the Section of
Hematology/Oncology, the Department of Medicine, University of Chicago,
Chicago, IL; and the Howard Hughes Medical Institute, the Department of
Biology, Massachusetts Institute of Technology, Cambridge, MA.
Therapy-related acute myeloid leukemia and myelodysplastic syndrome
(t-AML and MDS) are severe late complications of treatment with
genotoxic chemotherapeutic agents. Children with neurofibromatosis type
1 (NF1) are predisposed to malignant myeloid disorders that are
associated with inactivation of the NF1 tumor suppressor gene in the leukemic clone. Recent clinical data suggest that NF1 might be
also associated with an increased risk of t-AML after treatment with
alkyating agents. To test this hypothesis, we administered cyclophosphamide or etoposide to cohorts of wild-type and heterozygous Nf1 knockout mice. Cyclophosphamide exposure cooperated
strongly with heterozygous inactivation of Nf1 in myeloid
leukemogenesis, while etoposide did not. Somatic loss of the normal
Nf1 allele correlated with clinical disease and was more common
in 129/Sv mice than in 129/Sv × C57BL/6 animals. Leukemic cells
showing loss of heterozygosity at Nf1 retained a structural
allele on each chromosome 11 homolog. These studies establish a novel
in vivo model of alkylator-induced myeloid malignancy that will
facilitate mechanistic and translational studies.
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