title: Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine andDepartment of Oncology, Hematology and Stem Cell Transplantation, Rheinisch-Westfaelische Technische Hochschule Aachen University Medical School, 52070 Aachen, Germany;
authors.forename: Behzad
authors.initials: B
authors.lastname: Kharabi Masouleh
authors.affiliation: Department of Laboratory Medicine and.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Laboratory Medicine and.
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.affiliation: Department of Laboratory Medicine and.
authors.forename: Lai N
authors.initials: LN
authors.lastname: Chan
authors.affiliation: Division of Hematology-Oncology, University of California, San Francisco, CA 94143;
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Logan
authors.affiliation: Children's Hospital Los Angeles, Los Angeles, CA 90027;
authors.forename: Mi Sook
authors.initials: MS
authors.lastname: Chang
authors.affiliation: Departments of Medicine andPharmacology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Laboratory Medicine and.
authors.forename: Srividya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Haibo
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10466.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Departments of Medicine andPharmacology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Phillip
authors.initials: P
authors.lastname: Koeffler
authors.affiliation: Department of Laboratory Medicine and markus.muschen@ucsf.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002648:Child; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D000074462:Positive Regulatory Domain I-Binding Factor 1; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology; D000071717:X-Box Binding Protein 1; D001616:beta-Galactosidase
chemical_list: C491123:BACH2 protein, human; C084103:BCL6 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D001616:beta-Galactosidase