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Cancers
Special Issues
Pathogenesis and Natural History of Myeloproliferative Neoplasms
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Pathogenesis and Natural History of Myeloproliferative Neoplasms

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 39513

Special Issue Editor

Dr. Marco Pizzi

E-Mail Website
Guest Editor
Pathology Unit, Department of Medicine—DIMED, University of Padova School of Medicine, 35128 Padova, Italy
Interests: neoplastic/non-neoplastic hematological disorders; myeloproliferative neoplasms; pediatric hematopathology; lymphoma

Special Issue Information

Dear Colleagues,

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hemopoietic stem cell disorders with unique clinical-pathological and molecular features. Over the last few decades, the field of MPNs has undergone dramatic changes as a consequence of a better understanding of their biology and natural history. These achievements also fostered the development of new therapies targeting MPN-related molecular derangements. MPNs are thus a paradigmatic example of how the integration of basic sciences and applied research expands our knowledge of human diseases and improves their clinical management.

The spectrum of MPNs includes Chronic Myeloid Leukemia (CML), Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Although no longer considered within the MPN category, mastocytoses are closely related entities. CML is a myeloid neoplasm skewed towards granulocytic differentiation. It is driven by the BCR-ABL1 fusion gene, which is usually associated with the chromosomal translocation t(9;22)(q34.1;q11.2)—also known as the Philadelphia chromosome. PV, ET, and PMF (collectively referred to as Philadelphia-chromosome-negative MPNs) share some pathogenic mechanisms and evolution patterns. PV is driven by JAK2 mutations, involving either exon 14 (V617F mutation) or, less frequently, exon 12. By contrast, ET and PMF are mutated in JAK2 (V617F), MPL, or CALR genes. Rare cases of ET and PMF lack any driver mutation and their pathogenesis is a matter of active investigation. Unlike conventional MPNs, mastocytoses are associated with KIT mutations and present as clonal mast cell proliferations with highly variable clinical behavior.

Within this framework, this Special Issue will address the pathogenesis, molecular biology, and natural history of both adult and pediatric MPNs. The evolving field of cutaneous and systemic mastocytoses will be considered, as well.

Dr. Marco Pizzi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Philadelphia-negative myeloproliferative neoplasms
  • Chronic myeloid leukemia
  • Pediatric myeloproliferative neoplasms
  • Mastocytosis

Published Papers (14 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 165 KiB  
Editorial
Crossing the Borders: An Integrated Approach to Myeloproliferative Neoplasms and Mastocytoses
by Marco Pizzi
Cancers 2021, 13(7), 1492; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071492 - 24 Mar 2021
Cited by 3 | Viewed by 1387
Abstract
Since the first description of Chronic Myeloid Leukemia (CML) as a “suppuration of the blood” in 1845 [...] Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)

Research

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13 pages, 1532 KiB  
Article
Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells
by Manuela Mancini, Cecilia Monaldi, Sara De Santis, Michela Rondoni, Cristina Papayannidis, Chiara Sartor, Antonio Curti, Samantha Bruno, Michele Cavo and Simona Soverini
Cancers 2022, 14(3), 738; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030738 - 31 Jan 2022
Viewed by 2771
Abstract
Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have [...] Read more.
Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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13 pages, 954 KiB  
Article
A Multidisciplinary Diagnostic Approach Reveals a Higher Prevalence of Indolent Systemic Mastocytosis: 15-Years’ Experience of the GISM Network
by Roberta Zanotti, Massimiliano Bonifacio, Cecilia Isolan, Ilaria Tanasi, Lara Crosera, Francesco Olivieri, Giovanni Orsolini, Donatella Schena and Patrizia Bonadonna
Cancers 2021, 13(24), 6380; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246380 - 20 Dec 2021
Cited by 16 | Viewed by 1783
Abstract
Systemic mastocytosis (SM) and other adult clonal mast cell disorders (CMD) are often underestimated, and their epidemiology data are scarce. We aimed at evaluating the impact of the activity of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona on the prevalence [...] Read more.
Systemic mastocytosis (SM) and other adult clonal mast cell disorders (CMD) are often underestimated, and their epidemiology data are scarce. We aimed at evaluating the impact of the activity of the Interdisciplinary Group for Study of Mastocytosis (GISM) of Verona on the prevalence and incidence of CMD. We examined the data of 502 adult patients diagnosed with CMD and residing in the Veneto Region, consecutively referred to GISM between 2006 and 2020. SM was diagnosed in 431 cases, while 71 patients had cutaneous mastocytosis or other CMD. Indolent SM represented the most frequent SM variant (91.0%), mainly with the characteristics of bone marrow mastocytosis (54.8%). The prevalence of SM in the adult population of the Veneto region and of the Verona province was 10.2 and 17.2/100,000 inhabitants, respectively. The mean incidence of new SM cases in Verona was 1.09/100,000 inhabitants/year. Hymenoptera venom allergy was the main reason (50%) leading to the CMD diagnosis. Osteoporosis, often complicated by fragility fractures, was present in 35% of cases, even in young patients, especially males. Our data show a higher prevalence and incidence of SM than previously reported, confirming that reference centers with multidisciplinary approach are essential for the recognition and early diagnosis of CMD. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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14 pages, 2999 KiB  
Article
Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies
by Magdalena M. Brune, Achim Rau, Mathis Overkamp, Tim Flaadt, Irina Bonzheim, Christian M. Schürch, Birgit Federmann, Stefan Dirnhofer, Falko Fend and Alexandar Tzankov
Cancers 2021, 13(22), 5605; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225605 - 09 Nov 2021
Cited by 3 | Viewed by 2061
Abstract
Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, [...] Read more.
Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, current concepts suggest a stepwise acquisition of (additional) somatic mutations—apart from the initial driver mutations—that trigger disease evolution. In this study we molecularly analyzed paired bone marrow samples of MPN and MDS/MPN patients with known progression and compared them to a control cohort of patients with stable disease course. Cases with progression displayed from the very beginning a higher number of mutations compared to stable ones, of which mutations in five (ASXL1, DNMT3A, NRAS, SRSF2 and TP53) strongly correlated with progression and/or transformation, even if only one of these genes was mutated, and this particularly applied to MPN. TET2 mutations were found to have a higher allelic frequency than the putative driver mutation in three progressing cases (“TET2-first”), whereas two stable cases displayed a TET2-positive subclone (“TET2-second”), supporting the hypothesis that not only the sum of mutations but also their order of appearance matters in the course of disease. Our data emphasize the importance of genetic testing in MPN and MDS/MPN patients in terms of risk stratification and identification of imminent disease progression. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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17 pages, 3526 KiB  
Article
Carfilzomib Enhances the Suppressive Effect of Ruxolitinib in Myelofibrosis
by Simone Claudiani, Clinton C. Mason, Dragana Milojkovic, Andrea Bianchi, Cristina Pellegrini, Antinisca Di Marco, Carme R. Fiol, Mark Robinson, Kanagaraju Ponnusamy, Katya Mokretar, Avirup Chowdhury, Michael Albert, Alistair G. Reid, Michael W. Deininger, Kikkeri Naresh, Jane F. Apperley and Jamshid S. Khorashad
Cancers 2021, 13(19), 4863; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194863 - 28 Sep 2021
Cited by 1 | Viewed by 2233
Abstract
As the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive [...] Read more.
As the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive action of ruxolitinib may be due to intrinsic or extrinsic mechanisms leading to activity of additional pro-survival genes or signalling pathways that function independently of JAK2/STAT5. To identify alternative therapeutic targets, we applied a pooled-shRNA library targeting ~5000 genes to a JAK2V617F-positive cell line under a variety of conditions, including absence or presence of ruxolitinib and in the presence of a bone marrow microenvironment-like culture medium. We identified several proteasomal gene family members as essential to HEL cell survival. The importance of these genes was validated in MF cells using the proteasomal inhibitor carfilzomib, which also enhanced lethality in combination with ruxolitinib. We also showed that proteasome gene expression is reduced by ruxolitinib in MF CD34+ cells and that additional targeting of proteasomal activity by carfilzomib enhances the inhibitory action of ruxolitinib in vitro. Hence, this study suggests a potential role for proteasome inhibitors in combination with ruxolitinib for management of MF patients. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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18 pages, 2289 KiB  
Article
The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR–ABL- and JAK2V617F-Positive MPN
by Stefan Tillmann, Kathrin Olschok, Sarah K. Schröder, Marlena Bütow, Julian Baumeister, Milena Kalmer, Vera Preußger, Barbora Weinbergerova, Kim Kricheldorf, Jiri Mayer, Blanka Kubesova, Zdenek Racil, Martina Wessiepe, Jörg Eschweiler, Susanne Isfort, Tim H. Brümmendorf, Walter Becker, Mirle Schemionek, Ralf Weiskirchen, Steffen Koschmieder and Nicolas Chatainadd Show full author list remove Hide full author list
Cancers 2021, 13(16), 4210; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164210 - 21 Aug 2021
Cited by 7 | Viewed by 3178
Abstract
Lipocalin 2 (LCN2), a proinflammatory mediator, is involved in the pathogenesis of myeloproliferative neoplasms (MPN). Here, we investigated the molecular mechanisms of LCN2 overexpression in MPN. LCN2 mRNA expression was 20-fold upregulated in peripheral blood (PB) mononuclear cells of chronic myeloid leukemia (CML) [...] Read more.
Lipocalin 2 (LCN2), a proinflammatory mediator, is involved in the pathogenesis of myeloproliferative neoplasms (MPN). Here, we investigated the molecular mechanisms of LCN2 overexpression in MPN. LCN2 mRNA expression was 20-fold upregulated in peripheral blood (PB) mononuclear cells of chronic myeloid leukemia (CML) and myelofibrosis (MF) patients vs. healthy controls. In addition, LCN2 serum levels were significantly increased in polycythemia vera (PV) and MF and positively correlated with JAK2V617F and mutated CALR allele burden and neutrophil counts. Mechanistically, we identified endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a main driver of LCN2 expression in BCR-ABL- and JAK2V617F-positive 32D cells. The UPR inducer thapsigargin increased LCN2 expression >100-fold, and this was not affected by kinase inhibition of BCR-ABL or JAK2V617F. Interestingly, inhibition of the UPR regulators inositol-requiring enzyme 1 (IRE1) and c-Jun N-terminal kinase (JNK) significantly reduced thapsigargin-induced LCN2 RNA and protein expression, and luciferase promoter assays identified nuclear factor kappa B (NF-κB) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1–JNK-NF-κB–C/EBP axis is a major driver of LCN2 expression in MPN, and targeting UPR and LCN2 may represent a promising novel therapeutic approach in MPN. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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Graphical abstract

11 pages, 887 KiB  
Article
Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms
by Evan M. Braunstein, Hang Chen, Felicia Juarez, Fanghan Yang, Lindsay Tao, Igor Makhlin, Donna M. Williams, Shruti Chaturvedi, Aparna Pallavajjala, Theodoros Karantanos, Renan Martin, Elizabeth Wohler, Nara Sobreira, Christopher D. Gocke and Alison R. Moliterno
Cancers 2021, 13(13), 3246; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133246 - 29 Jun 2021
Cited by 4 | Viewed by 2167
Abstract
Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates [...] Read more.
Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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17 pages, 13230 KiB  
Article
T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker
by Magda Zanelli, Giuseppe G. Loscocco, Elena Sabattini, Maurizio Zizzo, Francesca Sanguedolce, Luigi Panico, Daniela Fanni, Raffaella Santi, Cecilia Caprera, Cristiana Rossi, Alessandra Soriano, Alberto Cavazza, Alessandro Giunta, Cristina Mecucci, Alessandro M. Vannucchi, Stefano A. Pileri and Stefano Ascani
Cancers 2021, 13(12), 3102; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123102 - 21 Jun 2021
Cited by 7 | Viewed by 2119
Abstract
Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), a group of diseases with gene fusion resulting in overexpression of an aberrant tyrosine kinase or cytokine receptor. The correct identification of this category has relevant therapeutic [...] Read more.
Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), a group of diseases with gene fusion resulting in overexpression of an aberrant tyrosine kinase or cytokine receptor. The correct identification of this category has relevant therapeutic implications. LIM domain only 2 (LMO2) is overexpressed in most T-LBL, but not in immature TdT-positive T-cells in the thymus and in indolent T-lymphoblastic proliferations (iT-LBP). Methods and Results: We retrospectively evaluated 11 cases of T-LBL occurring in the context of M/LNs-Eo. Clinical, histological, immunohistochemical and molecular features were collected and LMO2 immunohistochemical staining was performed. The critical re-evaluation of these cases confirmed the diagnosis of T-LBL with morphological, immunohistochemical and molecular features consistent with T-LBL occurring in M/LNs-Eo. Interestingly, LMO2 immunohistochemical analysis was negative in 9/11 cases, whereas only 2 cases revealed a partial LMO2 expression with a moderate and low degree of intensity, respectively. Conclusions: LMO2 may represent a potentially useful marker to identify T-LBL developing in the context of M/LNs-Eo. In this setting, T-LBL shows LMO2 immunohistochemical profile overlapping with cortical thymocytes and iT-LBP, possibly reflecting different molecular patterns involved in the pathogenesis of T-LBL arising in the setting of M/LNs-Eo. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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Review

Jump to: Editorial, Research, Other

23 pages, 7660 KiB  
Review
Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms
by Maria Teresa Bochicchio, Valeria Di Battista, Pietro Poggio, Giovanna Carrà, Alessandro Morotti, Mara Brancaccio and Alessandro Lucchesi
Cancers 2022, 14(4), 972; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040972 - 15 Feb 2022
Cited by 1 | Viewed by 2844
Abstract
Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the [...] Read more.
Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connections among signal transduction pathways highlighted in neoplastic cells suggest new strategies to overcome neoplastic cell adaptation. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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14 pages, 322 KiB  
Review
Essential Thrombocythemia in Children and Adolescents
by Maria Caterina Putti, Irene Bertozzi and Maria Luigia Randi
Cancers 2021, 13(23), 6147; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236147 - 06 Dec 2021
Cited by 6 | Viewed by 3189
Abstract
This paper reviews the features of pediatric essential thrombocythemia (ET). ET is a rare disease in children, challenging pediatric and adult hematologists alike. The current WHO classification acknowledges classical Philadelphia-negative MPNs and defines diagnostic criteria, mainly encompassing adult cases. The presence of one [...] Read more.
This paper reviews the features of pediatric essential thrombocythemia (ET). ET is a rare disease in children, challenging pediatric and adult hematologists alike. The current WHO classification acknowledges classical Philadelphia-negative MPNs and defines diagnostic criteria, mainly encompassing adult cases. The presence of one of three driver mutations (JAK2V617F, CALR, and MPL mutations) represent the proof of clonality typical of ET. Pediatric ET cases are thus usually confronted by adult approaches. These can fit only some patients, because only 25–40% of cases present one of the driver mutations. The diagnosis of hereditary, familial thrombocytosis and the exclusion of reactive/secondary thrombocytosis must be part of the diagnostic process in children and can clarify most of the negative cases. Still, many children present a clinical, histological picture of ET, with a molecular triple wild-type status. Moreover, prognosis seems more benign, at least within the first few decades of follow-up. Thrombotic events are rare, and only minor hemorrhages are ordinarily observed. As per the management, the need to control symptoms must be balanced with the collateral effects of lifelong drug therapy. We conclude that these differences concert a compelling case for a very careful therapeutic approach and advocate for the importance of further cooperative studies. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
21 pages, 4271 KiB  
Review
The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases
by Marco Pizzi, Giorgio Alberto Croci, Marco Ruggeri, Silvia Tabano, Angelo Paolo Dei Tos, Elena Sabattini and Umberto Gianelli
Cancers 2021, 13(22), 5666; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225666 - 12 Nov 2021
Cited by 11 | Viewed by 5546
Abstract
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of one or more myeloid lineages in the bone marrow. The classification and diagnostic criteria of MPNs have undergone relevant changes over the years, reflecting the [...] Read more.
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of one or more myeloid lineages in the bone marrow. The classification and diagnostic criteria of MPNs have undergone relevant changes over the years, reflecting the increased awareness on these conditions and a better understanding of their biological and clinical-pathological features. The current World Health Organization (WHO) Classification acknowledges four main sub-groups of MPNs: (i) Chronic Myeloid Leukemia; (ii) classical Philadelphia-negative MPNs (Polycythemia Vera; Essential Thrombocythemia; Primary Myelofibrosis); (iii) non-classical Philadelphia-negative MPNs (Chronic Neutrophilic Leukemia; Chronic Eosinophilic Leukemia); and (iv) MPNs, unclassifiable (MPN-U). The latter are currently defined as MPNs with clinical-pathological findings not fulfilling the diagnostic criteria for any other entity. The MPN-U spectrum traditionally encompasses early phase MPNs, terminal (i.e., advanced fibrotic) MPNs, and cases associated with inflammatory or neoplastic disorders that obscure the clinical-histological picture. Several lines of evidence and clinical practice suggest the existence of additional myeloid neoplasms that may expand the spectrum of MPN-U. To gain insight into such disorders, this review addresses the history of MPN classification, the evolution of their diagnostic criteria and the complex clinical-pathological and biological features of MPN-U. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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18 pages, 1744 KiB  
Review
Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants
by Elena Sabattini, Marco Pizzi, Claudio Agostinelli, Clara Bertuzzi, Carlo Alberto Sagramoso Sacchetti, Francesca Palandri and Umberto Gianelli
Cancers 2021, 13(21), 5531; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215531 - 04 Nov 2021
Cited by 3 | Viewed by 2503
Abstract
Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 [...] Read more.
Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 or myeloproliferative leukemia or CALReticulin genes, which are the primary drivers of the diseases, as well as defined diagnostic criteria and biomarkers in most cases. Progression is defined by the development or worsening of marrow fibrosis or the progressive increase in the marrow blast percentage. Progression is often related to additional genetic aberrations, although some can already be detected during the chronic phase. Detailed scoring systems for clinical usage that are mostly applied in patients with primary myelofibrosis have been defined, and the most recent ones include cytogenetic and molecular parameters with prognostic significance. Additional different clinic-pathologic changes have been reported that may occur during the course of the disease and that are, at present, classified as WHO-defined types of progression, although they likely represent such an event. The present review is meant to provide an updated overview on progression in Ph-chromosome-negative MPN, with a major focus on the pathologic side. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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22 pages, 845 KiB  
Review
Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios
by Francesca Palandri, Massimo Breccia, Valerio De Stefano and Francesco Passamonti
Cancers 2021, 13(19), 4750; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194750 - 23 Sep 2021
Cited by 8 | Viewed by 2410
Abstract
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for [...] Read more.
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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20 pages, 1771 KiB  
Systematic Review
The Prevalence of TET2 Gene Mutations in Patients with BCR-ABL-Negative Myeloproliferative Neoplasms (MPN): A Systematic Review and Meta-Analysis
by Yuh Cai Chia, Md Asiful Islam, Phil Hider, Peng Yeong Woon, Muhammad Farid Johan, Rosline Hassan and Marini Ramli
Cancers 2021, 13(12), 3078; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123078 - 20 Jun 2021
Cited by 10 | Viewed by 3361
Abstract
Multiple recurrent somatic mutations have recently been identified in association with myeloproliferative neoplasms (MPN). This meta-analysis aims to assess the pooled prevalence of TET2 gene mutations among patients with MPN. Six databases (PubMed, Scopus, ScienceDirect, Google Scholar, Web of Science and Embase) were [...] Read more.
Multiple recurrent somatic mutations have recently been identified in association with myeloproliferative neoplasms (MPN). This meta-analysis aims to assess the pooled prevalence of TET2 gene mutations among patients with MPN. Six databases (PubMed, Scopus, ScienceDirect, Google Scholar, Web of Science and Embase) were searched for relevant studies from inception till September 2020, without language restrictions. The eligibility criteria included BCR-ABL-negative MPN adults with TET2 gene mutations. A random-effects model was used to estimate the pooled prevalence with 95% confidence intervals (CIs). Subgroup analyses explored results among different continents and countries, WHO diagnostic criteria, screening methods and types of MF. Quality assessment was undertaken using the Joanna Briggs Institute critical appraisal tool. The study was registered with PROSPERO (CRD42020212223). Thirty-five studies were included (n = 5121, 47.1% female). Overall, the pooled prevalence of TET2 gene mutations in MPN patients was 15.5% (95% CI: 12.1–19.0%, I2 = 94%). Regional differences explained a substantial amount of heterogeneity. The prevalence of TET2 gene mutations among the three subtypes PV, ET and MF were 16.8%, 9.8% and 15.7%, respectively. The quality of the included studies was determined to be moderate–high among 83% of the included studies. Among patients with BCR-ABL-negative MPN, the overall prevalence of TET2 gene mutations was 15.5%. Full article
(This article belongs to the Special Issue Pathogenesis and Natural History of Myeloproliferative Neoplasms)
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