Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome
Year: 2017
Type: article
Abstract: Significance Children with Down syndrome are at increased risk for B-cell acute lymphoblastic leukemia (DS-ALL), often expressing cytokine receptor-like factor 2 (CRLF2). Here we studied matched diagnosis and relapse DS-ALLs to understand the pathogenesis of relapse. We confirm that enhanced JAK-STAT signaling frequently “drives” CRLF2 pos DS-ALL at diagnosis, but discovered that clones with JAK mutations are unstable, suggesting that they also endowed the transformed cells with vulnerabilities. We find USP9X loss in up to 25% of CRLF2 pos ALLs, and demonstrate that its ablation decreases the toxic effect of JAK2 hypersignaling. Thus, in CRLF2 pos ALLs JAK-STAT signaling is often buffered by loss of USP9X. These results have therapeutic implications because they suggest that ALL cells can tolerate a limited range of JAK-STAT signaling.
Authors: Omer Schwartzman, Angela Maria Savino, Michael Gombert, Chiara Palmi, Gunnar Cario, Martin Schrappe, Cornelia Eckert, Arend von Stackelberg, Jin-Yan Huang, Michal Hameiri-Grossman, Smadar Avigad, Geertruy te Kronnie, Ifat Geron, Yehudit Birger, Avigail Rein, Giulia Zarfati, Ute Fischer, Zohar Mukamel, Martin Stanulla, Andrea Biondi, Giovanni Cazzaniga, Amedeo Vetere, Bridget K. Wagner, Zhu Chen, Sai-Juan Chen, Amos Tanay, Arndt Borkhardt, Shai Izraeli
Institutions: Tel Aviv University, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Weizmann Institute of Science, Heinrich Heine University Düsseldorf, University of Milano-Bicocca, University Hospital Schleswig-Holstein, Charité – Universitätsmedizin Berlin, Shanghai Jiao Tong University, Ruijin Hospital, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Schneider Children's Medical Center, University of Padua, Medizinische Hochschule Hannover, Broad Institute, Howard Hughes Medical Institute
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Howard Hughes Medical Institute
OpenAlex ID: W2611874825