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AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis

2015; Impact Journals LLC; Volume: 6; Issue: 24 Linguagem: Inglês

10.18632/oncotarget.4136

1949-2553

Jino Park, Michaela Schlederer, Martin Schreiber, Ryan J. Ice, Olaf Merkel, Martin Bilban, Sebastian Hofbauer, Soo‐Jin Kim, Joseph Addison, Jie Zou, Chunyan Ji, Silvia T. Bunting, Zhengqi Wang, Menachem Shoham, Gang Huang, Zsuzsanna Bagó-Horváth, Laura F. Gibson, Yon Rojanasakul, Scot C. Remick, Alexey V. Ivanov, Elena N. Pugacheva, Kevin D. Bunting, Richard Moriggl, Lukas Kenner, William Tse,

Acute Myeloid Leukemia Research

// Jino Park 1 , Michaela Schlederer 2,12 , Martin Schreiber 3 , Ryan Ice 4,5 , Olaf Merkel 6 , Martin Bilban 7 , Sebastian Hofbauer 3 , Soojin Kim 1 , Joseph Addison 4,5 , Jie Zou 8 , Chunyan Ji 8 , Silvia T. Bunting 9 , Zhengqi Wang 9 , Menachem Shoham 10 , Gang Huang 11 , Zsuzsanna Bago-Horvath 12 , Laura F. Gibson 4 , Yon Rojanasakul 4,13 , Scot Remick 4 , Alexey Ivanov 4,5 , Elena Pugacheva 4,5 , Kevin D. Bunting 9 , Richard Moriggl 2,14 , Lukas Kenner 2,12,15,* and William Tse 1,* 1 James Graham Brown Cancer Center, Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA 2 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 3 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 4 Mary Babb Randolph Cancer Center, West Virginia University Health Science Center, Morgantown, WV, USA 5 Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV, USA 6 National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany 7 Department of Laboratory Medicine, Medical University of Vienna and Core Facility Genomics, Core Facilities, Medical University of Vienna, Vienna, Austria 8 Department of Hematology, Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, PR China 9 Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA 10 Case Western University School of Medicine, Cleveland, OH, USA 11 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 12 Clinical Institute for Pathology, Medical University Vienna, Austria 13 Department of Pharmaceutical Science, West Virginia University School of Medicine, Morgantown, WV, USA 14 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria 15 Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria * These authors have contributed equally to this work Correspondence to: Lukas Kenner, email: // William Tse, email: // Keywords : AF1q, TCF7, CD44, Wnt, metastasis Received : March 02, 2015 Accepted : April 21, 2015 Published : June 07, 2015 Abstract AF1q is an MLL fusion partner that was identified from acute myeloid leukemia (AML) patients with t (1; 11) (q21; q23) chromosomal abnormality. The function of AF1q is not yet fully known, however, elevated AF1q expression is associated with poor clinical outcomes in various malignancies. Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. In xenograft models, enforced AF1q expression in breast cancer cells also promotes liver metastasis and lung colonization. In a cohort of 63 breast cancer patients, higher percentages of AF1q-positive cancer cells in primary sites were associated with significantly poorer overall survival (OS), disease-free survival (DFS), and brain metastasis-free survival (b-MFS). Using paired primary/metastatic samples from the same patients, we demonstrate that AF1q-positive breast cancer cells become dynamically dominant in the metastatic sites compared to the primary sites. Our findings indicate that breast cancer cells with a hyperactive AF1q/TCF7/CD44 regulatory axis in the primary sites may represent “metastatic founder cells” which have invasive properties.