Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions

Jia, Ruochen; Královics, Róbert

doi:10.1007/s12185-019-02778-9

Cited by 18 publications

(14 citation statements)

References 122 publications

(156 reference statements)

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“…We see an enrichment of genes that are known to be bona fide STAT5 targets. Major signaling networks are also known to feed into the JAK–STAT signaling 17 . The prominent ones that have emerged in the transcriptome data are categorized into oncogenic signaling list.…”

Section: Discussionmentioning

confidence: 99%

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Hematopoietic expression of a chimeric murine‐human CALR oncoprotein allows the assessment of anti‐CALR antibody immunotherapies in vivo

Achyutuni

Nivarthi

Majoros³

et al. 2021

American J Hematol

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Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes are known to be three prominent MPN disease drivers. Mutant CALR (mutCALR) is an oncoprotein that interacts with and activates the thrombopoietin receptor (MPL) and represents an attractive target for targeted therapy of CALR mutated MPN. We generated a transgenic murine model with conditional expression of the human mutant exon 9 (del52) from the murine endogenous Calr locus. These mice develop essential thrombocythemia like phenotype with marked thrombocytosis and megakaryocytosis. The disease exacerbates with age showing prominent signs of splenomegaly and anemia. The disease is transplantable and mutCALR stem cells show proliferative advantage when compared to wild type stem cells. Transcriptome profiling of hematopoietic stem cells revealed oncogenic and inflammatory gene expression signatures. To demonstrate the applicability of the transgenic animals for immunotherapy, we treated mice with monoclonal antibody raised against the human mutCALR. The antibody treatment lowered platelet and stem cell counts in mutant mice. Secretion of mutCALR did not constitute a significant antibody sink. This animal model not only recapitulates human MPN but also serves as a relevant model for testing immunotherapeutic strategies targeting epitopes of the human mutCALR.

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Section: Discussionmentioning

confidence: 99%

“…Major signaling networks are also known to feed into the JAK-STAT signaling. 17 The prominent ones that have emerged in the transcriptome data are categorized into oncogenic signaling list. One of the hallmarks of cancer is deregulation of cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic expression of a chimeric murine‐human CALR oncoprotein allows the assessment of anti‐CALR antibody immunotherapies in vivo

Achyutuni

Nivarthi

Majoros³

et al. 2021

American J Hematol

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“…The ORR was lower in MF patients than in PV and ET patients [35,42]. In contrast to PV and ET, MF is a far more advanced disease with additional non-driver mutations [15]. Some studies have reported that the presence of additional non-driver mutations affects the response to IFN treatment [37].…”

Section: Review Of Recent Ifn Data In Mfmentioning

confidence: 95%

“…Disease progression is in the biological continuum from the early stages of cancer, such as ET and PV, to the advanced myelofibrosis stage and impending leukemic transformation [12]. Additional mutations, aside from the drive mutations (JAK2, CALR, and MPL), emerge during this evolution [15].…”

Section: Background For the Treatment Of Mpn With Ifnmentioning

confidence: 99%

The clinical role of interferon alpha in Philadelphia-negative myeloproliferative neoplasms

Yoon

Won

2021

Blood Res

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Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell malignancies. Chronic inflammation and a dysregulated immune system are central to the pathogenesis and progression of MPNs. Interferon alpha (IFNα) was first used for the treatment of MPNs approximately 40 years ago. It has significant antiviral effects and plays a role in anti-proliferative, pro-apoptotic, and immunomodulatory responses. IFNα is an effective drug that can simultaneously induce significant rates of clinical, hematological, molecular, and histopathological responses, suggesting that the disease may be cured in some patients. However, its frequent dosage and toxicity profile are major barriers to its widespread use. Pegylated IFNα (peg-IFNα), and more recently, ropeginterferon alpha-2b (ropeg-IFNα-2b), are expected to overcome these drawbacks. The objective of this article is to discuss the clinical role of IFNα in Philadelphia-negative MPNs through a review of recent studies. In particular, it is expected that new IFNs, such as peg-IFNα and ropeg-IFNα-2b, with lower rates of discontinuation due to fewer adverse effects, will play important clinical roles.

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“…All driver mutations of MPNs result in a constitutive activation of the JAK2 pathway. In particular the activation of this signal downstream of the thrombopoietin receptor MPL is a common feature of essential thrombocytopenia (ET) and primary myelofibrosis (PMF) [18]. This activation can reliably be modeled by overexpression of thrombopoietin (ThPO) in HSPCs.…”

Section: Employing Murine Models and Patient Materials To Dissect The Sequence Of Fibrotic Transformation On The Single-cell Levelmentioning

confidence: 99%

From cell to cell: Identification of actionable targets in bone marrow fibrosis using single-cell technologies

Leimkühler

Costa

Schneider

2021

Experimental Hematology

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Single-cell technologies have rapidly developed in recent years and have already had a significant impact on the research into myeloproliferative neoplasms. The increasing number of publicly available data sets allows characterization of the bone marrow niche in patients and mouse models at unprecedented resolution. Single-cell RNA sequencing has successfully been used to identify and characterize disease-driving cell populations and to identify the alarmin S100A8/A9 as an important mediator of myelofibrosis and potent therapeutic target. It is now possible to execute a streamlined set of experiments to specifically identify and validate actionable target genes functionally with the advance of reliable in vivo models and the possibility of conducting single-cell analyses with a minimal amount of patient material. The advent of large-scale analyses of both hematopoietic and nonhematopoietic bone marrow cells will allow comprehensive network analyses guiding an increasingly detailed mapping of the MPN interactome.

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Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions

Cited by 18 publications

References 122 publications

Hematopoietic expression of a chimeric murine‐human CALR oncoprotein allows the assessment of anti‐CALR antibody immunotherapies in vivo

Hematopoietic expression of a chimeric murine‐human CALR oncoprotein allows the assessment of anti‐CALR antibody immunotherapies in vivo

The clinical role of interferon alpha in Philadelphia-negative myeloproliferative neoplasms

From cell to cell: Identification of actionable targets in bone marrow fibrosis using single-cell technologies

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