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Mechanistic Rationale for Targeting the Unfolded Protein Response in Pre-B

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Mechanistic Rationale for Targeting the Unfolded Protein Response in Pre-B Mechanistic rationale for targeting the unfolded PNAS PLUS protein response in pre-B acute lymphoblastic leukemia Behzad Kharabi Masouleha,c, Huimin Genga, Christian Hurtza, Lai N. Chana, Aaron C. Loganb, Mi Sook Changd, Chuanxin Huange,f, Srividya Swaminathana, Haibo Sung, Elisabeth Paiettah, Ari M. Melnicke,f, Phillip Koefflerg, and Markus Müschena,1 aDepartment of Laboratory Medicine and bDivision of Hematology–Oncology, University of California, San Francisco, CA 94143; cDepartment of Oncology, Hematology and Stem Cell Transplantation, Rheinisch-Westfaelische Technische Hochschule Aachen University Medical School, 52070 Aachen, Germany; dChildren’s Hospital Los Angeles, Los Angeles, CA 90027; Departments of eMedicine and fPharmacology, Weill Cornell Medical College, New York, NY 10065; gCedars Sinai Medical Center, Los Angeles, CA 90048; and hDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY 10466 Edited by Owen N. Witte, Howard Hughes Medical Institute, University of California, Los Angeles, CA, and approved April 18, 2014 (received for review January 20, 2014) The unfolded protein response (UPR) pathway, a stress-induced autophosphorylation and oligomerization and induces cleavage signaling cascade emanating from the endoplasmic reticulum (ER), and splicing of XBP1 by its endoribonuclease (RNase) domain, regulates the expression and activity of molecules including BiP resulting in the removal of a 26-nucleotide intron. This frame (HSPA5), IRE1 (ERN1), Blimp-1 (PRDM1), and X-box binding protein shift modification leads to expression of a longer, highly active 1 (XBP1). These molecules are required for terminal differentiation splice variant (XBP1-s) (9), responsible for the regulation of a of B cells into plasma cells and expressed at high levels in plasma variety of downstream targets to relieve ER stress. Activation cell-derived multiple myeloma. Although these molecules have of the UPR by ER stress has been linked to the transition of no known role at early stages of B-cell development, here we mature surface Ig-dependent B cells to Ig-secreting plasma cells show that their expression transiently peaks at the pre–B-cell re- that no longer express Ig on the surface. An important role in ceptor checkpoint. Inducible, Cre-mediated deletion of Hspa5, — this transition is played by Ig heavy chain-binding protein (BiP) MEDICAL SCIENCES Prdm1 Xbp1 , and consistently induces cellular stress and cell death also known as heat shock 70-kDa protein 5 (HSPA5) and Grp78— – in normal pre-B cells and in pre B-cell acute lymphoblastic leuke- which chaperones folding of Ig heavy, but not light, chain proteins BCR-ABL1 NRASG12D mia (ALL) driven by - and oncogenes. Mecha- (10). A previous study also demonstrated that IRE1 (ERN1) is nistically, expression and activity of the UPR downstream effector – required during V(D)J recombination at the transition from pro- XBP1 is regulated positively by STAT5 and negatively by the B-cell to pre-B cells (11). specific transcriptional repressors BACH2 and BCL6. In two clinical XBP1 Here we provide genetic evidence for the emerging concept trials for children and adults with ALL, high mRNA levels at that the UPR molecules ERN1 and HSPA5, as well as their the time of diagnosis predicted poor outcome. A small molecule downstream effectors PRDM1 and XBP1, are not only critical inhibitor of ERN1-mediated XBP1 activation induced selective cell for the transition from surface Ig-dependent B cells to Ig- death of patient-derived pre-B ALL cells in vitro and significantly secreting plasma cells, but also regulate the pre–B-cell stage, when prolonged survival of transplant recipient mice in vivo. Collec- tively, these studies reveal that pre-B ALL cells are uniquely vul- nerable to ER stress and identify the UPR pathway and its Significance downstream effector XBP1 as novel therapeutic targets to over- come drug resistance in pre-B ALL. The unfolded protein response (UPR) mitigates endoplasmic reticulum (ER) stress. In this regard, ER stress-inducing agents erminal B-cell differentiation is regulated through two sets were found to be highly active in a clinical trial for children Tof antagonizing transcription factors: paired box gene 5 with relapsed acute lymphoblastic leukemia (ALL), a disease (PAX5), BTB and CNC homology 1, basic leucine zipper tran- derived from transformed pre-B cells. To understand the effi- scription factor 2 (BACH2), and BCL6 maintain B-cell identity cacy of ER stress-inducing agents in pre-B ALL, we studied the relevance of the UPR pathway in genetic and patient-derived of postgerminal center B cells (1), whereas the transcription factor (xenograft) models of human pre-B ALL. Our studies revealed PR domain containing 1, with ZNF domain (PRDM1) (also known an unrecognized vulnerability of both normal pre-B cells and as B-lymphocyte-induced maturation protein 1; BLIMP1) and pre-B cell-derived ALL cells to genetic or pharmacological block- X-box binding protein 1 (XBP1) drive plasma cell differentiation – ade of the UPR pathway. Our results establish a mechanistic ra- (2 4). The plasma cell transcription factor XBP1 and its upstream tionale for the treatment of children with pre-B ALL with agents regulator PRDM1 have been extensively studied in plasma cell that block the UPR pathway and induce ER stress. differentiation and the plasma cell malignancy multiple myeloma (5, 6), but not in early B-cell development or leukemias and lym- Author contributions: B.K.M. and M.M. designed research; B.K.M., C. Hurtz, L.N.C., M.S.C., phomas representing early stages of B-cell differentiation. Surpris- C. Huang, S.S., and H.S. performed research; A.C.L., E.P., A.M.M., and P.K. contributed new ingly, endoplasmic reticulum (ER) stress-inducing agents were reagents/analytic tools; B.K.M., H.G., L.N.C., M.S.C., C. Huang, S.S., H.S., E.P., and A.M.M. recently found to be highly active in a clinical trial for children analyzed data; and B.K.M. and M.M. wrote the paper. with relapsed acute lymphoblastic leukemia (ALL) (7), a disease The authors declare no conflict of interest. derived from transformed pre-B cells. This article is a PNAS Direct Submission. XBP1 is highly expressed in multiple myeloma and plasma Data deposition: Microarray data are available from the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE5314, GSE34941, GSE28460, cells, where it mitigates ER stress through engagement of the GSE11877, GSE20987, GSE30883, GSE19599, GSM488979, GSE13411, GSE12453, GSE53684, unfolded protein response (UPR). The UPR network consists of and GSE53683). See also Supplemental S3h-k: www.stjuderesearch.org/data/ALL3. three major branches including Inositol-requiring enzyme 1a 1To whom correspondence should be addressed. E-mail: [email protected]. α (IRE1 , ERN1), PKR-like ER kinase, and activating transcrip- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tion factor 6 (ATF6) (8). ERN1 is activated by ER stress through 1073/pnas.1400958111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1400958111 PNAS Early Edition | 1of10 Downloaded by guest on September 28, 2021 Ig heavy-chain variable region genes are rearranged and Ig heavy with strong up-regulation of the cell-cycle checkpoint regulators chains are expressed for the first time. Whereas recent studies Arf (Cdkn2a) and p21 (Cdkn1a; underlined in Fig. 1A). Micro- have identified XBP1 as a therapeutic target in multiple myeloma, array gene expression analysis was validated by single-gene we demonstrate that pre-B ALL cells are distinctly sensitive to quantitative RT (qRT)-PCR (SI Appendix, Fig. S2). Within 4 d of ER stress and pharmacological inhibition of XBP1. Pre-B ALL Hspa5 deletion, ∼50% of IL-7–dependent pre-B cells (Fig. 1C) arises from a transformed pre-B cell and represents the most and >70% of BCR-ABL1–transformed pre-B ALL cells (Fig. frequent type of cancer in children (12). Frequent oncogenic 1D) underwent cell death. Deletion of Hspa5 in BCR-ABL1– lesions in pre-B ALL include BCR-ABL1 (present in ∼30% of transformed pre-B ALL cells in vivo resulted in a drastic re- adult ALL) (13) and hyperactivating mutations of RAS genes duction of leukemia burden, as measured by luciferase bio- (in ∼50% of childhood pre-B ALL) (14). Small-molecule in- imaging (Fig. 1E) and prolonged overall survival of transplant hibitors targeting the RNase domain of ERN1 prevent activation recipient mice (Fig. 1F). In these experiments, 1 million lucif- of XBP1 and have disease-modifying activity in multiple mye- erase-labeled Hspa5fl/fl BCR-ABL1 pre-B ALL cells carrying loma (15, 16). Here we show that small-molecule inhibition of either tamoxifen-inducible GFP-tagged Cre (Cre; n = 9) or a ERN1/XBP1 represents a promising novel approach to overcome GFP-tagged empty vector (EV) control (n = 9) were injected drug resistance in pre-B ALL. (i.v.) into each sublethally irradiated (2 Gy) NOD/SCID mouse. Although deletion of Hspa5 significantly extended overall sur- Results vival of recipient mice (P = 0.028; Fig. 1F), recipient mice in both Hspa5 (Ig Heavy-Chain Binding Protein) Is Required for the Survival groups eventually developed terminal disease and had to be killed. and Malignant Transformation of Pre-B Cells. To elucidate the In the analysis of bone marrows and spleens from transplant re- − + function of UPR-related molecules in both normal pre-B and cipient mice we distinguished infiltrating CD45.1 CD45.2 leu- + − transformed pre-B ALL cells, we first focused on the ER chap- kemia cells from CD45.1 CD45.2 host cells. Interestingly, + erone heat shock 70-kDa protein 5 (HSPA5) (17), which miti- virtually all CD45.2 ALL cells expressed the GFP-tagged EV gates ER stress upstream of the ER sensor ERN1 (IRE-1).
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