Circulating Calreticulin Is Increased in Myelofibrosis: Correlation with Interleukin-6 Plasma Levels, Bone Marrow Fibrosis, and Splenomegaly

Sollazzo, Daria; Forte, Dorian; Polverelli, Nicola; Perricone, Margherita; Romano, Marco; Luatti, Simona; Vianelli, Nicola; Cavo, Michèle; Palandri, Francesca; Catani, Lucia

doi:10.1155/2016/5860657

Cited by 25 publications

(24 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, it is noteworthy that these pharmacokinetics studies were performed in healthy subjects, who probably would not have exhibited inflammation-related altered physiologic functions, such as IL-6-mediated repression of hepatic detoxifying pathways. By contrast, patients suffering from myeloproliferative neoplasms or rheumatoid arthritis, which correspond to present clinical indications for ruxolitinib and tofacitinib, respectively, commonly exhibit increased plasma levels of IL-6 ( Coki c et al, 2015;do Prado et al, 2016;Sollazzo et al, 2016). Pharmacokinetic studies centered on such patients are probably required therefore to verify the hypothesis that marketed JAK inhibitors, including not only ruxolitinib and tofacitinib, but also baricitinib, very recently approved in European Union for rheumatoid arthritis treatment (Richez et al, 2017), may cause idDDIs through antagonizing the IL-6/JAK/STAT pathway.…”

Section: Regulation Of P450 and Transporter Expression By Ruxolitinibmentioning

confidence: 99%

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

et al. 2017

View full text Add to dashboard Cite

The inflammatory cytokine interleukin (IL)-6, which basically activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) signaling pathway, is well known to repress expression of hepatic cytochromes P-450 (P450s) and transporters. Therapeutic proteins, like monoclonal antibodies targeting IL-6 or its receptor, have consequently been demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract the repressing effects of IL-6 toward hepatic detoxifying systems. Ruxolitinib was found to fully inhibit IL-6-mediated repression of P450 (CYP1A2, CYP2B6, and CYP3A4) and transporter (NTCP, OATP1B1, and OCT1) mRNA levels in primary human hepatocytes and differentiated hepatoma HepaRG cells. Such effects were dose-dependent, with ruxolitinib EC values around 1.0-1.2 M and thus close to ruxolitinib plasma levels that can be reached in patients. Moreover, they were associated with concomitant restoration of P450 and drug transporter activities in IL-6-exposed HepaRG cells. By contrast, ruxolitinib failed to suppress the repression of drug-detoxifying protein mRNA levels caused by IL-1 The JAK inhibitor and anti-rheumatoid arthritis compound tofacitinib was additionally found to reverse IL-6-mediated suppression of P450 and transporter mRNA expressions. Taken together, our results demonstrated that small drugs acting as JAK inhibitors, like ruxolitinib, counteract IL-6-mediated repression of drug-metabolizing enzymes and drug transporters in cultured human hepatocytes. These JAK inhibitors may consequently be hypothesized to restore hepatic detoxification capacity for patients suffering from inflammatory diseases, which may in turn cause idDDIs.

show abstract

Section: Regulation Of P450 and Transporter Expression By Ruxolitinibmentioning

confidence: 99%

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Furthermore, CRT is known as a tumor-associated antigen (TAA) for its significantly increased expression in various tumor cells (e.g., melanoma) and also the presence of soluble CRT (sCRT) in body fluids of patients with different types of cancers ( 3 – 5 ). Tumor immunobiological studies uncovered evidence suggesting positive roles for CRT in the control of tumor development.…”

Section: Introductionmentioning

confidence: 99%

Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo

Gong

Chen

et al. 2017

Front. Immunol.

View full text Add to dashboard Cite

Calreticulin (CRT), a multifunctional Ca2+-binding glycoprotein mainly located in the endoplasmic reticulum, is a tumor-associated antigen that has been shown to play protective roles in angiogenesis suppression and anti-tumor immunity. We previously reported that soluble CRT (sCRT) was functionally similar to heat shock proteins or damage-associated molecular patterns in terms of ability to activate myeloid cells and elicit strong inflammatory cytokine production. In the present study, B16 melanoma cell lines expressing recombinant CRT fragment 39-272 (sCRT/39-272) in secreted form (B16-CRT), or recombinant enhanced green fluorescence protein (rEGFP) (B16-EGFP), were constructed for investigation on the roles of sCRT in tumor development. When s.c. inoculated into C57BL/6 mice, the B16-CRT cells were significantly more aggressive (in terms of solid tumor growth rate) than B16-EGFP controls in a TLR4- and myeloid-derived suppressor cells (MDSC)-dependent manner. The B16-CRT-bearing mice showed increased Gr1+ MDSC infiltration in tumor tissues, accelerated proliferation of CD11b+Ly6G+Ly6Clow (G-MDSC) precursors in bone marrow, and higher percentages of G-MDSCs in spleen and blood, which was mirrored by decreased percentage of dendritic cells (DC) in periphery. In in vitro studies, recombinant sCRT/39-272 was able to promote migration and survival of tumor-derived MDSCs via interaction with TLR4, inhibit MDSC differentiation into DC, and also elicit expression of inflammatory proteins S100A8 and S100A9 which are essential for functional maturation and chemotactic migration of MDSCs. Our data provide solid evidence for CRT as a double-edged sword in tumor development.

show abstract

“…However, the amount of mutant proteins in the cell supernatants seemed too low to explain the difference of expression level between WT and mutant proteins in the cell lysates. Moreover, Sollazzo et al observed a similar level of plasmatic CALR between JAK2and CALR-mutated MPN patients [36], suggesting that the secretion of mutant CALR proteins is not massive. Accordingly, when using the Myc-6His tagged forms of CALR, we detected significant amounts of WT CALR in the extracellular medium, probably because the Myc-6His tag prevented the ER-retention by the KDEL motif.…”

Section: Discussionmentioning

confidence: 94%

The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

Mansier

Prouzet‐Mauléon

Jégou

et al. 2019

Cancers

View full text Add to dashboard Cite

Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.

show abstract

Circulating Calreticulin Is Increased in Myelofibrosis: Correlation with Interleukin-6 Plasma Levels, Bone Marrow Fibrosis, and Splenomegaly

Cited by 25 publications

References 29 publications

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo

The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

Contact Info

Product

Resources

About