| Here we report the cloning and initial characterization of a mutation in Mcm4 (Mcm4D573H) that arose spontaneously in our mouse breeding colony. This allele acts dominantly and causes highly penetrant T-cell leukemia/lymphoma early in life, so we named this mouse model Spontaneous dominant leukemia ( Sdl). MCM4 is part of a heterohexamer (MCM2-7) that serves as the eukaryotic DNA replicative helicase and is highly conserved throughout all eukaryotic species. The Mcm4D573H allele results in DNA replication defects, genomic instability, and leukemia that often contains intragenic deletions in Notch1. Total and DNA bound levels of MCMs are not decreased, in stark contrast to other murine cancer models with mutations in Mcms. In addition to its potential to contribute to deciphering the DNA replication mechanism, Sdl is useful as a preclinical model for testing novel therapeutic agents. We used leukemic Sdl and Sleeping Beauty mice to test if the radioiodinated phospholipid ether (PLE) analogue CLR1404, and its fluorescent companion compound, CLR1501, accumulate in tumor cells in these models. CLR1501 does accumulate in hematopoietic cells in leukemic mice by flow cytometry, and can also access leukemia cells in sanctuary sites. Positron emission tomography and computed tomography showed that 124I-CLR1404 successfully imaged hematopoietic organs that contained leukemia cells. Our results indicate that further studies to determine if CLR1404 is useful in imaging and treating hematologic neoplasms are warranted. |
