title: [Genetic heterogeneity in transient abnormal myelopoiesis].
abstract: Leukemia arises through an evolutionary process of somatic mutation and selection. Transient abnormal myelopoiesis (TAM) is a clonal pre-leukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism underlying leukemogenesis, a xenograft model of TAM was established using NOG mice. Serial engraftment after cell transplantation from a TAM patient who developed ML-DS a year later showed the self-renewal capacity of these cells. We detected a GATA1 mutation but no copy number alterations (CNAs) in the primary patient sample by conventional genomic sequencing and CNA profiling. However, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, both of which are clinically associated with ML-DS. Detailed genetic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with various leukemia-initiating potentials already exist in the neonatal TAM phase, and that ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model could be a valuable tool for gaining insight into the processes underlying leukemogenesis.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saida
mesh_terms: D000818:Animals; D004314:Down Syndrome / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D007955:Leukemoid Reaction / Q000235:genetics*; D009154:Mutation / Q000235:genetics*
chemical_list: D050982:GATA1 Transcription Factor