Year: 2018
Type: article
Abstract: A substantial subset of patients with T cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumbs to their disease. JDP2 encodes a bZIP protein that has been implicated as a T-ALL oncogene from insertional mutagenesis studies in mice, but its role in human T-ALL pathogenesis has remained obscure. Here we show that JDP2 is aberrantly expressed in a subset of T-ALL patients and is associated with poor survival. JDP2 is required for T-ALL cell survival, as its depletion by short hairpin RNA knockdown leads to apoptosis. Mechanistically, JDP2 regulates prosurvival signaling through direct transcriptional regulation of MCL1. Furthermore, JDP2 is one of few oncogenes capable of initiating T-ALL in transgenic zebrafish. Notably, thymocytes from rag2:jdp2 transgenic zebrafish express high levels of mcl1 and demonstrate resistance to steroids in vivo. These studies establish JDP2 as a novel oncogene in high-risk T-ALL and implicate overexpression of MCL1 as a mechanism of steroid resistance in JDP2-overexpressing cells.
DOI: 10.1084/jem.20170484
Authors: Marc R. Mansour, Shuning He, Zhaodong Li, Riadh Lobbardi, Brian J. Abraham, Clemens Hug, Sunniyat Rahman, Theresa E. Leon, You-Yi Kuang, Mark W. Zimmerman, Traci Blonquist, Evisa Gjini, Alejandro Gutierrez, Qin Tang, Laura Garcia-Perez, Karin Pike-Overzet, Lars Anders, Alla Berezovskaya, Yi Zhou, Leonard I. Zon, Donna Neuberg, Adele K. Fielding, Frank J.T. Staal, David M. Langenau, Takaomi Sanda, Richard A. Young, A. Thomas Look
Institutions: Harvard University, Dana-Farber Cancer Institute, University College London, Massachusetts General Hospital, Harvard Stem Cell Institute, Whitehead Institute for Biomedical Research, Chinese Academy of Fishery Sciences, Boston Children's Hospital, Howard Hughes Medical Institute, Leiden University Medical Center, National University of Singapore, Cancer Science Institute of Singapore, Massachusetts Institute of Technology
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Howard Hughes Medical Institute, Damon Runyon Cancer Research Foundation, Alex's Lemonade Stand Foundation for Childhood Cancer, Gabrielle's Angel Foundation for Cancer Research, Broad Institute, Cancer Research UK, National Institute for Health and Care Research, Kay Kendall Leukaemia Fund, University College London, National Research Foundation Singapore, Bloodwise, Blood Cancer UK, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute
Awards: Discovery of New Targets and Pathways for T-ALL Therapy, G2703706394, G2901481919, G3104076719, G3312584095, G3381839230, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G3703537882, Molecular Pathways to Thynmic Lymphoma and Leukemia, Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia, G421865639, G4278917193, Therapeutic Index of Acute Lymphoblastic Leukemia, G508888048, Embryonic Hematopoiesis, G7159667525, G8082910050, G8491803085, G9000150487, G9000215840, G9000315942, G9000330065, Targetable epigenetic and transcriptional mechanisms in melanoma thatshape the microenvironment, G997771125
OpenAlex ID: W2809743846