The genetic basis of susceptibility to therapy-related leukemia in mice.

摘要

Treatment-related acute myeloid leukemia (t-AML) arises as a result of treating primary malignancies with alkylator chemotherapy drugs and has a poor prognosis. Genetic background influences the risk of acquiring t-AML, yet little is known about susceptibility factors. To identify candidate risk factors, cohorts of twenty inbred mouse strains were treated with N-ethyl-N-nitrosourea (ENU), a potent alkylating agent in mice. Six of these mouse strains were susceptible to alkylator-induced leukemia. SWR/J mice were the most susceptible in this relatively small screen. We expanded on that study to characterize SWR/J mice as a susceptible strain to t-AML using 245 mice. Mice were treated with different permutations of steroid treatment to determine the effect they would have on leukemia numbers. In addition to the susceptible strains, quantitative trait loci mapping was used on the initial study to identify genetic components responsible for the leukemic phenotype. This analysis revealed two significant peaks of interest on chromosomes 3 and 14. The 1 Mb region on chromosome 3 contains six genes, one of which was myeloid leukemia factor 1 (Mlf1). In humans, MLF1 waspreviously identified for its involvement in a chromosomal translocation with nucleophosmin (NPM) that is restricted to AML and myelodysplastic (MDS) patients. We show that MLF1 is pro-apoptotic and decreases the viability of hematopoietic cells.