Myeloproliferative blood cancers as a human neuroinflammation model for development of Alzheimer’s disease: evidences and perspectives

Hasselbalch, Hans Carl; Skov, Vibe; Kjær, Lasse; Sørensen, Torben Lykke; Ellervik, Christina; Wienecke, Troels

doi:10.1186/s12974-020-01877-3

Cited by 8 publications

(7 citation statements)

References 73 publications

(145 reference statements)

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“…Herein, we argue for the rationales and perspectives for initiating clinical studies on the safety and efficacy of rIFN-β -a forgotten drug in the treatment of cancer, but hopefully soon to be revived for the treatment of patients with MPNs, in whom repeated ischemic strokes contribute significantly to morbidity and mortality. From this perspective, repurposing rIFN-β in the treatment of MPNs is expected to open a new horizon for MPN patients, taking into account that rIFN-β may not only be highly efficacious in controlling elevated blood cell counts, but may also play a neuroprotective role—not only against the development of Alzheimer’s disease [ 129 ], but also in ischemic stroke prevention [ 210 ].…”

Section: Discussionmentioning

confidence: 99%

“…The potential of rIFN-β in the treatment of neuroinflammatory diseases other than MS, such as Alzheimer’s disease (AD), has also been investigated [ 127 , 128 ]. Since AD and MPNs share several pathogenetic mechanisms, MPNs have most recently been described as “A Human Neuroinflammation Model for The Development of Alzheimer’s Disease” [ 129 ]. Herein, after briefly depicting the successful history of rIFN-α in the treatment MPNs, we tell the story of rIFN-β in other diseases and discuss the rationales and perspectives for launching studies on the safety and efficacy of pegylated IFN-β in the treatment of MPNs.…”

Section: Introductionmentioning

confidence: 99%

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

Hasselbalch

Skov

Kjær

et al. 2022

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

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

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“…Most lately, the MPNs have been described as a human neuroinflammation model for the development of Alzheimer's disease. 33 Accordingly, it is intriguing to use MPNs as a "Human inflammation model" on drusen/AMD development as well, implying CLI in MPNs to elicit drusen formation, which "triggers" more CLI, creating a vicious cycle.…”

Section: Introductionmentioning

confidence: 99%

Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

et al. 2022

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Background The hematopoietic stem cell disorders, myeloproliferative neoplasms (MPNs), are characterised by chronic low-grade inflammation (CLI). Recently, we showed that patients with MPNs have an increased prevalence of drusen and age-related macular degeneration (AMD), and drusen prevalence seemed associated with higher CLI. Studying MPNs may reveal more about drusen pathophysiology. This study investigated CLI further by measuring cytokine levels and complement system markers, comparing these between patients with MPNs and AMD.Methods This cross-sectional study, between July 2018 and November 2020 conducted at Zealand University Hospital (ZUH) − Roskilde, Denmark, included 29 patients with neovascular AMD (nAMD), 28 with intermediate-stage AMD (iAMD), 62 with MPNs (35 with drusen -MPNd and 27 with healthy retinas -MPNn). With flow cytometry, we measured complement-regulatory-proteins (Cregs). With immunoassays, we investigated cytokine levels combined into a summary-inflammation-score (SIS).Findings The MPNd and nAMD groups had similar SIS, significantly higher than the MPNn and iAMD groups. Additionally, we found SIS to increase over the MPN biological continuum from early cancer stage, essential thrombocytaemia (ET), over polycythaemia vera (PV) to the late-stage primary myelofibrosis (PMF). MPNs showed signs of complement dysregulation, with Cregs expression lower in PV than ET and PMF and even lower in PV patients with drusen.Interpretation This study suggests that MPNd have a higher CLI than MPNn and may indicate systemic CLI to play a greater part in, and even initiate drusen formation. We suggest using MPNs as a "Human Inflammation Model" of drusen development. The CLI in MPNs elicits drusen formation, triggering more CLI creating a vicious cycle, increasing the risk of developing AMD.

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“…The pathogenetic role of inflammation has been emphasized in the initiation and progression of disease, as well as in the development of the typical signs/symptoms of MPNs, such as anemia, constitutional symptoms, thrombosis, splenomegaly, BM fibrosis and pulmonary hypertension, thus actively contributing to morbidity and mortality [ 29 , 30 , 31 , 32 ]. Moreover, for some authors, MPNs epitomize a full-fledged inflammatory model of human cancer development, as suggested by the evidence of abnormal cytokine production and an association with several inflammatory/autoimmune diseases and second cancers [ 33 , 34 , 35 , 36 , 37 , 38 ]. In this model, chronic inflammation is hypothesized to induce the first oncogenic hit in the HSC by causing mutations and genomic instability, eventually leading to MPN emergence [ 39 , 40 ].…”

Section: Hit the Road Jak: Jak-stat Signaling At The Dangerous Cromentioning

confidence: 99%

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Nasillo

Riva

Paolini

et al. 2021

IJMS

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The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

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Myeloproliferative blood cancers as a human neuroinflammation model for development of Alzheimer’s disease: evidences and perspectives

Cited by 8 publications

References 73 publications

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

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

Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

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