Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

Chatain, Nicolas; Koschmieder, Steffen; Jost, Edgar

doi:10.3390/cancers12082250

Cited by 12 publications

(12 citation statements)

References 143 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The direct interaction of the clonal with normal HSPCs or endothelial and mesenchymal stromal cells plays a central role in inflammation, thrombosis, and extramedullary hematopoiesis [26]. Therefore, we investigated the expression of cell adhesion molecules and observed an upregulation of ITGB2, ITGB7, SELP, and SELPLG in all subtypes.…”

Section: Nf-κb and Tnfα Pathways Are Upregulated In Cd34 + Cells In Late Stages Of Mpnmentioning

confidence: 96%

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

Myeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing–associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN. Graphical abstract

show abstract

Section: Nf-κb and Tnfα Pathways Are Upregulated In Cd34 + Cells In Late Stages Of Mpnmentioning

confidence: 96%

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Apart from the aforementioned genetic causes, inflammatory processes were not only assigned a role in triggering symptoms in MPN patients, but also in progression to overt MF or BP-MPN. The extensive interaction between the malignant clone, non-malignant hematopoietic and non-hematopoietic cells in the BM microenvironment (including mesenchymal stromal cells [MSCs]), and inflammatory cytokines or reactive oxygen species (ROS) is a powerful driving force of fibrotic remodeling (as reviewed in [ 41 ]). In this process, dysplastic megakaryocytes are of particular importance: they secrete a plethora of inflammatory cytokines which evoke the reprogramming of endothelial cells or MSCs into myofibroblasts, and these myofibroblasts are key factors in fibrotic tissue formation.…”

Section: Etiology Of Mpn Progressionmentioning

confidence: 99%

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Baumeister

Chatain

Sofias

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.

show abstract

“…In recent years, chronic inflammation has been proposed to be of utmost importance in the pathogenesis of MPNs [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], as both a trigger and a driver of clonal evolution and disease progression. In this context, MPNs have been described as “A Human Inflammation Model” and “A Human Inflammation Model for Cancer Development”, in which the malignant clone steadily expands in a vicious self-perpetuating cycle fueled by the malignant clone itself [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

Hasselbalch

Skov

Kjær

et al. 2022

Cancers

View full text Add to dashboard Cite

About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies—e.g., immune-checkpoint inhibitors—are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)—i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis—and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-β (rIFN-β)—has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-β as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-β in patients with MPNs.

show abstract

Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

Cited by 12 publications

References 143 publications

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives

Contact Info

Product

Resources

About