TitleMechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsMasouleh, Behzad Kharabi, Geng Huimin, Hurtz Christian, Chan Lai N., Logan Aaron C., Chang Mi Sook, Huang ChuanXin, Swaminathan Srividya, Sun Haibo, Paietta Elisabeth, Melnick Ari M., Koeffler Phillip, and Müschen Markus
JournalProc Natl Acad Sci U S A
Volume111
Issue21
PaginationE2219-28
Date Published2014 May 27
ISSN1091-6490
KeywordsAdult, Animals, B-Lymphocytes, Base Sequence, Basic-Leucine Zipper Transcription Factors, beta-Galactosidase, Blotting, Western, Cell Differentiation, Child, Chromatin Immunoprecipitation, DNA-Binding Proteins, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Endoribonucleases, Flow Cytometry, Gene Deletion, Gene Expression Regulation, Heat-Shock Proteins, Heterografts, Humans, Kaplan-Meier Estimate, Mice, Microarray Analysis, Molecular Sequence Data, Positive Regulatory Domain I-Binding Factor 1, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-6, Real-Time Polymerase Chain Reaction, Regulatory Factor X Transcription Factors, Repressor Proteins, Sequence Analysis, RNA, Transcription Factors, Unfolded Protein Response, X-Box Binding Protein 1
Abstract

<p>The unfolded protein response (UPR) pathway, a stress-induced signaling cascade emanating from the endoplasmic reticulum (ER), regulates the expression and activity of molecules including BiP (HSPA5), IRE1 (ERN1), Blimp-1 (PRDM1), and X-box binding protein 1 (XBP1). These molecules are required for terminal differentiation of B cells into plasma cells and expressed at high levels in plasma cell-derived multiple myeloma. Although these molecules have no known role at early stages of B-cell development, here we show that their expression transiently peaks at the pre-B-cell receptor checkpoint. Inducible, Cre-mediated deletion of Hspa5, Prdm1, and Xbp1 consistently induces cellular stress and cell death in normal pre-B cells and in pre-B-cell acute lymphoblastic leukemia (ALL) driven by BCR-ABL1- and NRAS(G12D) oncogenes. Mechanistically, expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6. In two clinical trials for children and adults with ALL, high XBP1 mRNA levels at the time of diagnosis predicted poor outcome. A small molecule inhibitor of ERN1-mediated XBP1 activation induced selective cell death of patient-derived pre-B ALL cells in vitro and significantly prolonged survival of transplant recipient mice in vivo. Collectively, these studies reveal that pre-B ALL cells are uniquely vulnerable to ER stress and identify the UPR pathway and its downstream effector XBP1 as novel therapeutic targets to overcome drug resistance in pre-B ALL.</p>

DOI10.1073/pnas.1400958111
Alternate JournalProc Natl Acad Sci U S A
PubMed ID24821775
PubMed Central IDPMC4040579
Grant List101880 / / Wellcome Trust / United Kingdom
U10 CA021115 / CA / NCI NIH HHS / United States
R01 CA157644 / CA / NCI NIH HHS / United States
R01 CA172558 / CA / NCI NIH HHS / United States
R01CA169458 / CA / NCI NIH HHS / United States
R01CA139032 / CA / NCI NIH HHS / United States
R01CA137060 / CA / NCI NIH HHS / United States
R01 CA169458 / CA / NCI NIH HHS / United States
U10 CA037403 / CA / NCI NIH HHS / United States
U10 CA180820 / CA / NCI NIH HHS / United States
R01 CA139032 / CA / NCI NIH HHS / United States
R01CA157644 / CA / NCI NIH HHS / United States
U24 CA114737 / CA / NCI NIH HHS / United States
R01CA172558 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States
R01 CA137060 / CA / NCI NIH HHS / United States