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, Kevin M. Shannon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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 alkylating 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 x 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.

Original languageEnglish (US)
Pages (from-to)3617-3623
Number of pages7
JournalBlood
Volume93
Issue number11
DOIs
StatePublished - Jun 1 1999

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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