title: Comparative genomics reveals multistep pathogenesis of E2A-PBX1 acute lymphoblastic leukemia.
abstract: 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.
authors: Jesús
authors: J
authors: Duque-Afonso
authors: Jue
authors: J
authors: Feng
authors: Florian
authors: F
authors: Scherer
authors: Chiou-Hong
authors: CH
authors: Lin
authors: Stephen H K
authors: SH
authors: Wong
authors: Zhong
authors: Z
authors: Wang
authors: Masayuki
authors: M
authors: Iwasaki
authors: Michael L
authors: ML
authors: Cleary
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse; D050791:STAT Transcription Factors; C089847:E2A-Pbx1 fusion protein; D053612:Janus Kinases