Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia

Proc Natl Acad Sci U S A. 2014 May 27;111(21):E2219-28. doi: 10.1073/pnas.1400958111. Epub 2014 May 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology*
  • Base Sequence
  • Basic-Leucine Zipper Transcription Factors / pharmacology
  • Blotting, Western
  • Cell Differentiation / physiology
  • Child
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / pharmacology
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / physiology
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Flow Cytometry
  • Gene Deletion
  • Gene Expression Regulation / drug effects*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Heterografts
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Microarray Analysis
  • Molecular Sequence Data
  • Positive Regulatory Domain I-Binding Factor 1
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-bcl-6
  • Real-Time Polymerase Chain Reaction
  • Regulatory Factor X Transcription Factors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Sequence Analysis, RNA
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Unfolded Protein Response / drug effects*
  • Unfolded Protein Response / physiology
  • X-Box Binding Protein 1
  • beta-Galactosidase

Substances

  • BACH2 protein, human
  • BCL6 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Regulatory Factor X Transcription Factors
  • Repressor Proteins
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • beta-Galactosidase
  • molecular chaperone GRP78

Associated data

  • GEO/GSE11877
  • GEO/GSE12453
  • GEO/GSE13411
  • GEO/GSE19599
  • GEO/GSE20987
  • GEO/GSE28460
  • GEO/GSE30883
  • GEO/GSE34941
  • GEO/GSE5314
  • GEO/GSE53683
  • GEO/GSE53684
  • GEO/GSM488979