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

Behzad Kharabi Masouleh, Huimin Geng, Christian Hurtz, Lai N. Chan, Aaron C. Logan, Mi Sook Chang, Chuanxin Huang, Srividya Swaminathan, Haibo Sun, Elisabeth M. Paietta, Ari M. Melnick, Phillip Koeffler, Markus Müschen

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 NRASG12D 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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number21
DOIs
StatePublished - May 27 2014

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Unfolded Protein Response
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
B-Lymphoid Precursor Cells
Plasma Cells
Pre-B Cell Receptors
Cell Death
Endoplasmic Reticulum Stress
Multiple Myeloma
Oncogenes
Drug Resistance
Endoplasmic Reticulum
X-Box Binding Protein 1
Clinical Trials
Messenger RNA
Survival

ASJC Scopus subject areas

  • General

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Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia. / Masouleh, Behzad Kharabi; Geng, Huimin; Hurtz, Christian; Chan, Lai N.; Logan, Aaron C.; Chang, Mi Sook; Huang, Chuanxin; Swaminathan, Srividya; Sun, Haibo; Paietta, Elisabeth M.; Melnick, Ari M.; Koeffler, Phillip; Müschen, Markus.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 21, 27.05.2014.

Research output: Contribution to journalArticle

Masouleh, BK, Geng, H, Hurtz, C, Chan, LN, Logan, AC, Chang, MS, Huang, C, Swaminathan, S, Sun, H, Paietta, EM, Melnick, AM, Koeffler, P & Müschen, M 2014, 'Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 21. https://doi.org/10.1073/pnas.1400958111
Masouleh, Behzad Kharabi ; Geng, Huimin ; Hurtz, Christian ; Chan, Lai N. ; Logan, Aaron C. ; Chang, Mi Sook ; Huang, Chuanxin ; Swaminathan, Srividya ; Sun, Haibo ; Paietta, Elisabeth M. ; Melnick, Ari M. ; Koeffler, Phillip ; Müschen, Markus. / Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 21.
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