title: Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.
abstract: Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic 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 varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saida
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Kiminori
authors.initials: K
authors.lastname: Terui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: RuNan
authors.initials: R
authors.lastname: Wang
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Itaru
authors.initials: I
authors.lastname: Kato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morishima
authors.forename: Hisanori
authors.initials: H
authors.lastname: Fujino
authors.forename: Katsutsugu
authors.initials: K
authors.lastname: Umeda
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Hiramatsu
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D060965:Clonal Evolution / Q000502:physiology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000097:blood* / Q000150:complications* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D005078:Exchange Transfusion, Whole Blood; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D007955:Leukemoid Reaction / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D011289:Preleukemia / Q000235:genetics / Q000473:pathology / Q000628:therapy; D014183:Transplantation, Heterologous
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human