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

J 2021

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

TILLMANN, S., K. OLSCHOK, S. K. SCHRODER, M. BUTOW, J. BAUMEISTER et. al.

Basic information

Original name

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

Authors

TILLMANN, S. (276 Germany), K. OLSCHOK (276 Germany), S. K. SCHRODER (276 Germany), M. BUTOW (276 Germany), J. BAUMEISTER (276 Germany), M. KALMER (276 Germany), V. PREUSSGER (276 Germany), Barbora WEINBERGEROVÁ (203 Czech Republic, belonging to the institution), K. KRICHELDORF (276 Germany), Jiří MAYER (203 Czech Republic, belonging to the institution), Blanka KUBEŠOVÁ (203 Czech Republic, belonging to the institution), Zdeněk RÁČIL (203 Czech Republic, belonging to the institution), M. WESSIEPE (276 Germany), J. ESCHWEILER (276 Germany), S. ISFORT (276 Germany), T. H. BRUMMENDORF (276 Germany), W. BECKER (276 Germany), M. SCHEMIONEK (276 Germany), R. WEISKIRCHEN (276 Germany), S. KOSCHMIEDER (276 Germany) and N. CHATAIN (276 Germany, guarantor)

Edition

Cancers, BASEL, MDPI, 2021, 2072-6694

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.575

RIV identification code

RIV/00216224:14110/21:00122733

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3390/cancers13164210

UT WoS

000688911900001

Keywords in English

Lipocalin 2 (LCN2); NGAL; ER stress; UPR; MPN; BCR-ABL; IRE1

Abstract

V originále

Simple Summary Lipocalin 2 (LCN2) is a proinflammatory mediator increased in the blood of patients with myeloproliferative neoplasms (MPN) and other hematologic malignancies, significantly contributing to MPN disease initiation and progression. Here, we investigated the underlying mechanisms of LCN2 overexpression in MPN. We found a strong correlation between BCR-ABL and JAK2V617F driver oncogenes and LCN2 expression. Furthermore, LCN2 expression is strongly induced by endoplasmic reticulum (ER) stress, independent of oncogenic kinase activity. We identified the IRE1-JNK-NF-kappa B-C/EBP axis as a major mediator of ER stress-induced LCN2 expression. Our findings provide novel insights into the regulation of LCN2 and present a basis for innovative, targeted treatment approaches in MPN. 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-kappa B) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1-JNK-NF-kappa B-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.

Citovat

TILLMANN, S., K. OLSCHOK, S. K. SCHRODER, M. BUTOW, J. BAUMEISTER, M. KALMER, V. PREUSSGER, Barbora WEINBERGEROVÁ, K. KRICHELDORF, Jiří MAYER, Blanka KUBEŠOVÁ, Zdeněk RÁČIL, M. WESSIEPE, J. ESCHWEILER, S. ISFORT, T. H. BRUMMENDORF, W. BECKER, M. SCHEMIONEK, R. WEISKIRCHEN, S. KOSCHMIEDER and N. CHATAIN. The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN. Cancers. BASEL: MDPI, 2021, vol. 13, No 16, p. 1-18. ISSN 2072-6694. Available from: https://dx.doi.org/10.3390/cancers13164210.

@article{1801083,
   author = {Tillmann, S. and Olschok, K. and Schroder, S. K. and Butow, M. and Baumeister, J. and Kalmer, M. and Preussger, V. and Weinbergerová, Barbora and Kricheldorf, K. and Mayer, Jiří and Kubešová, Blanka and Ráčil, Zdeněk and Wessiepe, M. and Eschweiler, J. and Isfort, S. and Brummendorf, T. H. and Becker, W. and Schemionek, M. and Weiskirchen, R. and Koschmieder, S. and Chatain, N.},
   article_location = {BASEL},
   article_number = {16},
   doi = {http://dx.doi.org/10.3390/cancers13164210},
   keywords = {Lipocalin 2 (LCN2); NGAL; ER stress; UPR; MPN; BCR-ABL; IRE1},
   language = {eng},
   issn = {2072-6694},
   journal = {Cancers},
   title = {The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN},
   url = {https://www.mdpi.com/2072-6694/13/16/4210},
   volume = {13},
   year = {2021}
}

TY  - JOUR
ID  - 1801083
AU  - Tillmann, S. - Olschok, K. - Schroder, S. K. - Butow, M. - Baumeister, J. - Kalmer, M. - Preussger, V. - Weinbergerová, Barbora - Kricheldorf, K. - Mayer, Jiří - Kubešová, Blanka - Ráčil, Zdeněk - Wessiepe, M. - Eschweiler, J. - Isfort, S. - Brummendorf, T. H. - Becker, W. - Schemionek, M. - Weiskirchen, R. - Koschmieder, S. - Chatain, N.
PY  - 2021
TI  - The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN
JF  - Cancers
VL  - 13
IS  - 16
SP  - 1-18
EP  - 1-18
PB  - MDPI
SN  - 20726694
KW  - Lipocalin 2 (LCN2)
KW  - NGAL
KW  - ER stress
KW  - UPR
KW  - MPN
KW  - BCR-ABL
KW  - IRE1
UR  - https://www.mdpi.com/2072-6694/13/16/4210
N2  - Simple Summary Lipocalin 2 (LCN2) is a proinflammatory mediator increased in the blood of patients with myeloproliferative neoplasms (MPN) and other hematologic malignancies, significantly contributing to MPN disease initiation and progression. Here, we investigated the underlying mechanisms of LCN2 overexpression in MPN. We found a strong correlation between BCR-ABL and JAK2V617F driver oncogenes and LCN2 expression. Furthermore, LCN2 expression is strongly induced by endoplasmic reticulum (ER) stress, independent of oncogenic kinase activity. We identified the IRE1-JNK-NF-kappa B-C/EBP axis as a major mediator of ER stress-induced LCN2 expression. Our findings provide novel insights into the regulation of LCN2 and present a basis for innovative, targeted treatment approaches in MPN. 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-kappa B) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1-JNK-NF-kappa B-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.
ER  -

TILLMANN, S., K. OLSCHOK, S. K. SCHRODER, M. BUTOW, J. BAUMEISTER, M. KALMER, V. PREUSSGER, Barbora WEINBERGEROVÁ, K. KRICHELDORF, Jiří MAYER, Blanka KUBEŠOVÁ, Zdeněk RÁČIL, M. WESSIEPE, J. ESCHWEILER, S. ISFORT, T. H. BRUMMENDORF, W. BECKER, M. SCHEMIONEK, R. WEISKIRCHEN, S. KOSCHMIEDER and N. CHATAIN. The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN. \textit{Cancers}. BASEL: MDPI, 2021, vol.~13, No~16, p.~1-18. ISSN~2072-6694. Available from: https://dx.doi.org/10.3390/cancers13164210.

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