The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN

Stefan Tillmann; Kathrin Olschok; Sarah K Schröder; Marlena Bütow; Julian Baumeister; Milena Kalmer; Vera Preußger; Barbora Weinbergerova; Kim Kricheldorf; Jiri Mayer; Blanka Kubesova; Zdenek Racil; Martina Wessiepe; Jörg Eschweiler; Susanne Isfort; Tim H Brümmendorf; Walter Becker; Mirle Schemionek; Ralf Weiskirchen; Steffen Koschmieder; Nicolas Chatain

doi:10.3390/cancers13164210

The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN

Cancers (Basel). 2021 Aug 21;13(16):4210. doi: 10.3390/cancers13164210.

Authors

Stefan Tillmann^{1

2}, Kathrin Olschok^{1

2}, Sarah K Schröder^{2

3}, Marlena Bütow^{1

2}, Julian Baumeister^{1

2}, Milena Kalmer^{1

2}, Vera Preußger⁴, Barbora Weinbergerova⁵, Kim Kricheldorf^{1

2}, Jiri Mayer⁵, Blanka Kubesova⁵, Zdenek Racil^{5

6}, Martina Wessiepe⁷, Jörg Eschweiler⁸, Susanne Isfort^{1

2}, Tim H Brümmendorf^{1

2}, Walter Becker⁴, Mirle Schemionek^{1

2}, Ralf Weiskirchen^{2

3}, Steffen Koschmieder^{1

2}, Nicolas Chatain^{1

2}

Affiliations

¹ Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 520674 Aachen, Germany.
² Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany.
³ Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
⁴ Institute of Pharmacology and Toxicology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
⁵ Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, 625 00 Brno, Czech Republic.
⁶ Institute of Hematology and Blood Transfusion, 12820 Prague, Czech Republic.
⁷ Institute of Transfusion Medicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
⁸ Department of Orthopedic Surgery, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.

Abstract

Lipocalin 2 (LCN2), a proinflammatory mediator, is involved in the pathogenesis of myeloproliferative neoplasms (MPN). Here, we investigated the molecular mechanisms of LCN2 overexpression in MPN. LCN2 mRNA expression was 20-fold upregulated in peripheral blood (PB) mononuclear cells of chronic myeloid leukemia (CML) and myelofibrosis (MF) patients vs. healthy controls. In addition, LCN2 serum levels were significantly increased in polycythemia vera (PV) and MF and positively correlated with JAK2V617F and mutated CALR allele burden and neutrophil counts. Mechanistically, we identified endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a main driver of LCN2 expression in BCR-ABL- and JAK2V617F-positive 32D cells. The UPR inducer thapsigargin increased LCN2 expression >100-fold, and this was not affected by kinase inhibition of BCR-ABL or JAK2V617F. Interestingly, inhibition of the UPR regulators inositol-requiring enzyme 1 (IRE1) and c-Jun N-terminal kinase (JNK) significantly reduced thapsigargin-induced LCN2 RNA and protein expression, and luciferase promoter assays identified nuclear factor kappa B (NF-κB) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1-JNK-NF-κB-C/EBP axis is a major driver of LCN2 expression in MPN, and targeting UPR and LCN2 may represent a promising novel therapeutic approach in MPN.

Keywords: BCR-ABL; ER stress; IRE1; JAK2V617F; Lipocalin 2 (LCN2); MPN; NGAL; UPR.

Abstract

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