IWASAKI Masayuki    Department   Research Institutes and Facilities, Research Institutes and Facilities    Position   Assistant Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia.
Journal	Formal name：The Journal of clinical investigation Abbreviation：J Clin Invest ISSN code：15588238/00219738
Domestic / Foregin	Foregin
Volume, Issue, Page	125(9),pp.3667-80
Author and coauthor	Duque-Afonso Jesús, Feng Jue, Scherer Florian, Lin Chiou-Hong, Wong Stephen H K, Wang Zhong, Iwasaki Masayuki, Cleary Michael L
Publication date	2015/09
Summary	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