イワサキ　マサユキ   Iwasaki Masayuki   岩崎　正幸    所属   研究施設 研究施設    職種   講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia.
掲載誌名	正式名：The Journal of clinical investigation 略　 称：J Clin Invest ISSNコード：15588238/00219738
掲載区分	国外
巻・号・頁	125(9),pp.3667-80
著者・共著者	Duque-Afonso Jesús, Feng Jue, Scherer Florian, Lin Chiou-Hong, Wong Stephen H K, Wang Zhong, Iwasaki Masayuki, Cleary Michael L
発行年月	2015/09
概要	Acute lymphoblastic leukemia (ALL) is the most common childhood cancer; however, its genetic diversity limits investigation into the molecular pathogenesis of disease and development of therapeutic strategies. Here, we engineered mice that conditionally express the E2A-PBX1 fusion oncogene, which results from chromosomal translocation t(1;19) and is present in 5% to 7% of pediatric ALL cases. The incidence of leukemia in these mice varied from 5% to 50%, dependent on the Cre-driving promoter (Cd19, Mb1, or Mx1) used to induce E2A-PBX1 expression. Two distinct but highly similar subtypes of B cell precursor ALLs that differed by their pre-B cell receptor (pre-BCR) status were induced and displayed maturation arrest at the pro-B/large pre-B II stages of differentiation, similar to human E2A-PBX1 ALL. Somatic activation of E2A-PBX1 in B cell progenitors enhanced self-renewal and led to acquisition of multiple secondary genomic aberrations, including prominent spontaneous loss of Pax5. In preleukemic mice, conditional Pax5 deletion cooperated with E2A-PBX1 to expand progenitor B cell subpopulations, increasing penetrance and shortening leukemia latency. Recurrent secondary activating mutations were detected in key signaling pathways, most notably JAK/STAT, that leukemia cells require for proliferation. These data support conditional E2A-PBX1 mice as a model of human ALL and suggest targeting pre-BCR signaling and JAK kinases as potential therapeutic strategies.
DOI	10.1172/JCI81158
PMID	26301816