title: E2A-PBX1 Remodels Oncogenic Signaling Networks in B-cell Precursor Acute Lymphoid Leukemia.
abstract: There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. Mechanistically, E2A-PBX1 bound promoter regulatory regions and activated the transcription of its key target genes ZAP70, SYK, and LCK, which encode kinases upstream of PLCγ2. Depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise silencing of ZAP70, SYK, or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy with inhibitors of these kinases. Accordingly, inhibitors such as the SRC family kinase (SFK) inhibitor dasatinib reduced pPLCγ2 and inhibited proliferation of human and mouse preBCR+/E2A-PBX1+leukemias in vitro and in vivo Furthermore, combining small-molecule inhibition of SYK, LCK, and SFK showed synergistic interactions and preclinical efficacy in the same setting. Our results show how the oncogenic fusion protein E2A-PBX1 perturbs signaling pathways upstream of PLCγ2 and renders leukemias amenable to targeted therapeutic inhibition. Cancer Res; 76(23); 6937-49. ©2016 AACR.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Jesús
authors.initials: J
authors.lastname: Duque-Afonso
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Chiou-Hong
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California.
authors.forename: Kyuho
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wei
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.|Department of Pathology and Department of Medicine, New York University Langone Medical Center, New York, New York.
authors.forename: Jue
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Kurzer
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.|Department of Hematology and Oncology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Schneidawind
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Stephen Hon-Kit
authors.initials: SH
authors.lastname: Wong
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bassik
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California. mcleary@stanford.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; C089847:E2A-Pbx1 fusion protein