Special Issue "Myeloproliferative Neoplasms: From Genetic Landscape to Therapeutic Targets"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 August 2021).

Special Issue Editors

Prof. Marco Vitale
E-Mail Website
Guest Editor
Università degli Studi di Parma, Facoltà di Medicina e Chirurgia, Parma, Italy
Interests: hematopoietic stem cell differentiation; erythropoiesis; megakaryocytopoiesis; platelets; myeloproliferative neoplasms; cell signalling; protein kinase C
Dr. Elena Masselli
E-Mail Website
Guest Editor
Department of Medicine & Surgery, University of Parma, Parma, Italy
Interests: hematopoietic stem cell differentiation; megakaryocytopoiesis; platelets; myeloproliferative neoplasms; cytokines; polymorphisms

Special Issue Information

Dear Colleagues,

The biological, molecular and clinical landscape of Philadelphia-negative myeloproliferative neoplasms (MPNs) has dramatically changed in the last decades, leading to a better understanding of the pathophysiology of these disorders and to a significant improvement of the therapeutic armamentarium for MPN patients.

In addition to the so called “phenotypic-driver mutations”, the widespread adoption of next-generation sequencing technology has provided key insights into the molecular mechanisms of MPNs, leading to the identification of mutations in genes involved in epigenetic methylation, RNA splicing, transcriptional regulation and signal transduction, significantly affecting disease course and outcome. Moreover, genome wide association studies revealed that other genetic factors, such as germline predisposition factors, also impact the disease.

Different mouse models recapitulating the main features of these disorders have also been generated, enabling to define the role of each genetic lesion in determining the disease phenotype, the long-term effects of the single mutant gene and the function of MPN-initiating cells. All this information led to the implementation of patient risk stratification systems for tailored treatment options.

We currently know that all three MPNs, but primarily myelofibrosis (MF), are typified by aberrant megakaryocytopoiesis, and that the megakaryocytic clone is the main source of a plethora of cytokines responsible for local (bone marrow) and systemic inflammation. Indeed, MPNs are considered a model of onco-inflammatory disorders and, in this scenario, distinct MPNs could be more appropriately seen as a “biological continuum”, in which polycythemia vera (PV) and essential thrombocythemia (ET) represent early stages followed by an advanced, burnout phase (MF), that in turn may develop into secondary acute myeloid leukemia. The primary focus of this special issue will be to provide the state of the art of the genetic landscape of MPNs and of its inflammatory environment, to cover the recent advances in cell signaling alterations during the aberrant differentiation of the MPN hematopoietc stem cell and to discuss how all this impacts on therapeutic strategies based on new molecular targets.

Dr. Marco Vitale
Dr. Elena Masselli
Guest Editors

Manuscript Submission Information

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Keywords

  • Myeloproliferative Neoplasms
  • Myelofibrosis
  • Polycythemia Vera
  • Essential Thrombocythemia
  • Hematopoiesis
  • Megakaryocytopoiesis
  • CD34+ cells
  • TGF-beta
  • Mouse models
  • Cytokines
  • Somatic mutation
  • Prognostic models

Published Papers (6 papers)

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Research

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Article
Comparative Mutational Profiling of Hematopoietic Progenitor Cells and Circulating Endothelial Cells (CECs) in Patients with Primary Myelofibrosis
Cells 2021, 10(10), 2764; https://doi.org/10.3390/cells10102764 - 15 Oct 2021
Viewed by 359
Abstract
A role of endothelial cells (ECs) in Primary Myelofibrosis (PMF) was supposed since JAK2 mutation was found in endothelial precursor cells (EPCs) and in ECs captured by laser microdissection. By Cell Search method, the circulating endothelial cells (CECs) from 14 PMF patients and [...] Read more.
A role of endothelial cells (ECs) in Primary Myelofibrosis (PMF) was supposed since JAK2 mutation was found in endothelial precursor cells (EPCs) and in ECs captured by laser microdissection. By Cell Search method, the circulating endothelial cells (CECs) from 14 PMF patients and 5 healthy controls have been isolated and compared by NGS with CD34+Hematopoietic stem and progenitors cells (HSPCs) for panel of 54 myeloid-associated mutations. PMF patients had higher levels of CECs. No mutation was found in HSPCs and CECs from controls, while CECs from PMF patients presented several somatic mutations. 72% of evaluable patients shared at least one mutation between HSPCs and CECs. 2 patients shared the JAK2 mutation, together with ABL1, IDH1, TET2 and ASXL1, KMT2A, respectively. 6 out of 8 shared only NON MPN-driver mutations: TET2 and NOTCH1 in one case; individual paired mutations in TP53, KIT, SRSF2, NOTCH1 and WT1, in the other cases. In conclusion, 70% of PMF patients shared at least one mutation between HSPCs and CECs. These latter harbored several myeloid-associated mutations, besides JAK2V617F mutation. Our results support a primary involvement of EC in PMF and provide a new methodological approach for further studies exploring the role of the “neoplastic” vascular niche. Full article
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Review

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Review
The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome
Cells 2021, 10(10), 2597; https://doi.org/10.3390/cells10102597 - 29 Sep 2021
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Abstract
Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible [...] Read more.
Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy. This review covered the polymorphisms that have been variably associated to MPNs, discussing them in the functional perspective of the biological pathways involved. Finally, we reviewed host genetic determinants of clonal hematopoiesis, a pre-malignant state that may anticipate overt hematologic neoplasms including MPNs. Full article
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Review
The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters
Cells 2021, 10(9), 2316; https://doi.org/10.3390/cells10092316 - 04 Sep 2021
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Abstract
Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, [...] Read more.
Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in “education” and “crafting” of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers. Full article
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Review
Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms
Cells 2021, 10(8), 1962; https://doi.org/10.3390/cells10081962 - 02 Aug 2021
Cited by 1 | Viewed by 698
Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the [...] Read more.
Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may be used for monitoring of residual disease after transplantation and response to treatment. Second, mutation profile can be used, eventually in combination with cytogenetic, histopathologic, hematologic, and clinical variables, to risk stratify patients regarding thrombosis, overall survival, and rate of transformation to secondary leukemia. This review outlines the molecular landscape of MPN and critically interprets current information for their potential impact on patient management. Full article
Review
Next Generation Therapeutics for the Treatment of Myelofibrosis
Cells 2021, 10(5), 1034; https://doi.org/10.3390/cells10051034 - 27 Apr 2021
Cited by 1 | Viewed by 1586
Abstract
Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do [...] Read more.
Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis. Full article
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Other

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Perspective
A Novel Megakaryocyte Subpopulation Poised to Exert the Function of HSC Niche as Possible Driver of Myelofibrosis
Cells 2021, 10(12), 3302; https://doi.org/10.3390/cells10123302 - 25 Nov 2021
Viewed by 204
Abstract
Careful morphological investigations, coupled with experimental hematology studies in animal models and in in vitro human cultures, have identified that platelets are released in the circulation by mature megakaryocytes generated by hematopoietic stem cells by giving rise to lineage-restricted progenitor cells and then [...] Read more.
Careful morphological investigations, coupled with experimental hematology studies in animal models and in in vitro human cultures, have identified that platelets are released in the circulation by mature megakaryocytes generated by hematopoietic stem cells by giving rise to lineage-restricted progenitor cells and then to morphologically recognizable megakaryocyte precursors, which undergo a process of terminal maturation. Advances in single cell profilings are revolutionizing the process of megakaryocytopoiesis as we have known it up to now. They identify that, in addition to megakaryocytes responsible for producing platelets, hematopoietic stem cells may generate megakaryocytes, which exert either immune functions in the lung or niche functions in organs that undergo tissue repair. Furthermore, it has been discovered that, in addition to hematopoietic stem cells, during ontogeny, and possibly in adult life, megakaryocytes may be generated by a subclass of specialized endothelial precursors. These concepts shed new light on the etiology of myelofibrosis, the most severe of the Philadelphia negative myeloproliferative neoplasms, and possibly other disorders. This perspective will summarize these novel concepts in thrombopoiesis and discuss how they provide a framework to reconciliate some of the puzzling data published so far on the etiology of myelofibrosis and their implications for the therapy of this disease. Full article
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