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

Tillmann, Stefan; Olschok, Kathrin; Schröder, Sarah K.; Bütow, Marlena; Baumeister, Julian; Kalmer, Milena; Preußger, Vera; Weinbergerová, Barbora; Kricheldorf, Kim; Mayer, Jiřı́; Kubešová, Blanka; Ráčil, Zdeněk; Wessiepe, Martina; Eschweiler, Jörg; Isfort, Susanne; Bruemmendorf, Tim H.; Becker, Walter; Schemionek, Mirle; Weiskirchen, Ralf; Koschmieder, Steffen; Chatain, Nicolas

doi:10.3390/cancers13164210

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…LCN2 is a neutrophil gelatinase-associated lipocalin that plays a role in innate immunity and seems to be involved in multiple cellular processes, including maintenance of skin homeostasis, and suppression of invasiveness and metastasis. LCN2 is a proinflammatory mediator that contributes to MPNs initiation and progression [ 34 ]. It has been found elevated in the plasma of MPN patients [ 35 ] and cells with the p.V617F mutation cause DNA damage to adjacent normal cells through the secretion of this molecule [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic comparison of bone marrow CD34 + cells and peripheral blood neutrophils from ET patients with JAK2 or CALR mutations

Guijarro-Hernández,

Vizmanos

2023

BMC Genom Data

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Background Essential thrombocythemia (ET) is one of the most common types of Ph-negative myeloproliferative neoplasms, an infrequent group of blood cancers that arise from a CD34 + hematopoietic stem cell (HSC) in the bone marrow (BM) primarily due to driver mutations in JAK2, CALR or MPL. These aberrations result in an overproduction of mature myeloid cells in peripheral blood (PB). To date, no targeted therapies have been approved for ET patients, so the study of the molecular mechanisms behind the disease and the identification of new therapeutic targets may be of interest. For this reason, in this study, we have compared the transcriptomic profile of undifferentiated CD34 + cells and mature myeloid cells from ET patients (CALR and JAK2-mutated) and healthy donors deposited in publicly available databases. The study of the similarities and differences between these samples might help to better understand the molecular mechanisms behind the disease according to the degree of maturation of the malignant clone and the type of mutation and ultimately help identify new therapeutic targets for these patients. Results The results show that most of the altered hallmarks in neutrophils were also found in CD34 + cells. However, only a few genes showed a similar aberrant expression pattern in both types of cells. We have identified a signature of six genes common to patients with CALR and JAK2 mutations (BPI, CRISP3, LTF, MMP8, and PTGS1 upregulated, and PBXIP1 downregulated), a different signature of seven genes for patients with CALR mutations (BMP6, CEACAM8, ITK, LCN2, and PRG2 upregulated, and MAN1A1 and MME downregulated) and a signature of 13 genes for patients with JAK2 mutations (ARG1, CAST, CD177, CLEC5A, DAPP1, EPS15, IL18RAP, OLFM4, OLR1, RIOK3, SELP, and THBS1 upregulated, and IGHM downregulated). Conclusions Our results highlight transcriptomic similarities and differences in ET patients according to the degree of maturation of the malignant clone and the type of mutation. The genes and processes altered in both CD34 + cells and mature neutrophils may reveal altered sustained processes that could be studied as future therapeutic targets for ET patients.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic comparison of bone marrow CD34 + cells and peripheral blood neutrophils from ET patients with JAK2 or CALR mutations

Guijarro-Hernández,

Vizmanos

2023

BMC Genom Data

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“…Given the great interest in TGF-β1, LCN2, and CXCL1 in the pathobiology of myelofibrosis [ 8 , 40 , 41 ], the serum levels of these three inflammatory cytokines were compared by ELISA using larger cohorts of mice. In addition, in this set of experiments, Gata1 low Psel null (and Psel null mice) were analyzed as additional negative control.…”

Section: Resultsmentioning

confidence: 99%

Resident Self-Tissue of Proinflammatory Cytokines Rather Than Their Systemic Levels Correlates with Development of Myelofibrosis in Gata1low Mice

et al. 2022

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Serum levels of inflammatory cytokines are currently investigated as prognosis markers in myelofibrosis, the most severe Philadelphia-negative myeloproliferative neoplasm. We tested this hypothesis in the Gata1low model of myelofibrosis. Gata1low mice, and age-matched wild-type littermates, were analyzed before and after disease onset. We assessed cytokine serum levels by Luminex-bead-assay and ELISA, frequency and cytokine content of stromal cells by flow cytometry, and immunohistochemistry and bone marrow (BM) localization of GFP-tagged hematopoietic stem cells (HSC) by confocal microscopy. Differences in serum levels of 32 inflammatory-cytokines between prefibrotic and fibrotic Gata1low mice and their wild-type littermates were modest. However, BM from fibrotic Gata1low mice contained higher levels of lipocalin-2, CXCL1, and TGF-β1 than wild-type BM. Although frequencies of endothelial cells, mesenchymal cells, osteoblasts, and megakaryocytes were higher than normal in Gata1low BM, the cells which expressed these cytokines the most were malignant megakaryocytes. This increased bioavailability of proinflammatory cytokines was associated with altered HSC localization: Gata1low HSC were localized in the femur diaphysis in areas surrounded by microvessels, neo-bones, and megakaryocytes, while wild-type HSC were localized in the femur epiphysis around adipocytes. In conclusion, bioavailability of inflammatory cytokines in BM, rather than blood levels, possibly by reshaping the HSC niche, correlates with myelofibrosis in Gata1low mice.

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“…Our group and others have shown LCN2 to promote therapy resistance and tumor progression by inhibiting ferroptosis in multiple tumor types [30,41–46]. LCN2 inhibits ferroptosis by decreasing the levels of intracellular iron, thus leading to increased ROS clearance in the presence of chemotherapeutic agents [30,45].…”

Section: Discussionmentioning

confidence: 99%

Lipocalin 2 inhibits actin glutathionylation to promote invasion and migration

et al. 2023

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Invasive and metastatic tumor cells show an increase in migration and invasion, making the processes contributing to these phenotypes potential therapeutic targets. Lipocalin 2 (LCN2; also known as neutrophil gelatinase‐associated lipocalin) is a putative therapeutic target in multiple tumor types and promotes invasion and migration, although the mechanisms underlying these phenotypes are unclear. The data in this report demonstrate that LCN2 promotes actin polymerization, invasion, and migration by inhibiting actin glutathionylation. LCN2 inhibits actin glutathionylation by decreasing the levels of reactive oxygen species (ROS) and by reducing intracellular iron levels. Inhibiting LCN2 function leads to increased actin glutathionylation, decreased migration, and decreased invasion. These results suggest that LCN2 is a potential therapeutic target in invasive tumors.

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

Cited by 7 publications

References 46 publications

Transcriptomic comparison of bone marrow CD34 + cells and peripheral blood neutrophils from ET patients with JAK2 or CALR mutations

Transcriptomic comparison of bone marrow CD34 + cells and peripheral blood neutrophils from ET patients with JAK2 or CALR mutations

Resident Self-Tissue of Proinflammatory Cytokines Rather Than Their Systemic Levels Correlates with Development of Myelofibrosis in Gata1low Mice

Lipocalin 2 inhibits actin glutathionylation to promote invasion and migration

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