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BCR-ABL1 Negative Myeloproliferative Neoplasms
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BCR-ABL1 Negative Myeloproliferative Neoplasms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 37583

Special Issue Editor

Prof. Dr. Giuseppe A. Palumbo

E-Mail Website
Guest Editor
Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
Interests: MPNs; myelofibrosis (MF); Policitemia Vera (PV); essential thrombocytemia (TE); JAK2; calreticulin (CALR); MPL; JAK inhibitor (JAKi); NGS

Special Issue Information

Dear Colleagues,

BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem-cell-derived clonal myeloid diseases, featured by an inflammatory condition affecting patient quality of life and supporting tumor progression.

The presence of a driver mutation in the JAK2, CALR or MPL gene in the majority of patients plays a key role not only in diagnosis, but also in evaluation of prognosis that can be further modified by the eventual presence of other subclonal mutations.

Both driver and subclonal mutations are now taken into consideration in new prognostic scoring systems and may be better investigated using novel molecular biology techniques, such as next-generation sequence (NGS).

Finally, the discovery in MPN patients of mutations affecting JAK signaling as a major pathogenic mechanism of MPNs has prompted the development of JAK inhibitors (JAKi), which are now in the standard armamentarium to fight these diseases. Recently, other drugs targeting different cellular targets have been investigated with promising results, and combinatorial therapies with JAKi have begun to be envisioned. However, allogeneic bone marrow transplantation is still a mainstay in the therapy of young patients.

This Special Issue, “BCR-ABL1-Negative Myeloproliferative Neoplasms”, will cover a selection of recent research topics and current review articles in the field of diagnosis, prognosis, and therapy of these diseases.

Prof. Giuseppe A. Palumbo
Guest Editor

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Keywords

  • MPNs
  • myelofibrosis (MF)
  • Policitemia Vera (PV)
  • essential thrombocytemia (TE)
  • JAK2
  • calreticulin (CALR)
  • MPL
  • JAK inhibitor (JAKi)
  • NGS
  • target therapy

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Published Papers (6 papers)

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Research

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19 pages, 5701 KiB  
Article
Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients
by Michelino Di Rosa, Cesarina Giallongo, Alessandra Romano, Daniele Tibullo, Giovanni Li Volti, Giuseppe Musumeci, Ignazio Barbagallo, Rosa Imbesi, Paola Castrogiovanni and Giuseppe A. Palumbo
Int. J. Mol. Sci. 2020, 21(8), 2926; https://doi.org/10.3390/ijms21082926 - 22 Apr 2020
Cited by 11 | Viewed by 3601
Abstract
Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by stem-cell-derived clonal over-proliferation of mature myeloid lineages, bone marrow fibrosis, osteosclerosis, defective erythropoiesis, and pro-inflammatory cytokine over-expression. The aim of the present study was to highlight possible differences in the transcriptome among CD34 [...] Read more.
Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by stem-cell-derived clonal over-proliferation of mature myeloid lineages, bone marrow fibrosis, osteosclerosis, defective erythropoiesis, and pro-inflammatory cytokine over-expression. The aim of the present study was to highlight possible differences in the transcriptome among CD34+ cells from peripheral blood (PB) of PMF patients. Therefore, we merged two microarray datasets of healthy control subjects and PMF (34 JAK2V617F MUTATED and 28 JAK2 wild-type). The GO analysis of upregulated genes revealed enrichment for JAK2/STAT1 pathway gene set in PB CD34+ cells of PMF patients with and without the JAK2V617F mutation comparing to the healthy control subjects, and in particular a significant upregulation of immunoproteasome (IP)-belonging genes as PSMB8, PSMB9, and PSMB10. A more detailed investigation of the IFN-gamma (IFNG) pathway also revealed that IFNG, IRF1, and IFNGR2 were significantly upregulated in PB CD34+ cells of PMF patients carrying the mutation for JAK2V617F compared to JAK2 wild-type PMF patients. Finally, we showed an upregulation of HLA-class I genes in PB CD34+ cells from PMF JAK2V617F mutated patients compared to JAK2 wild-type and healthy controls. In conclusion, our results demonstrate that IPs and IFNG pathways could be involved in PMF disease and in particular in patients carrying the JAK2V617F mutation. Full article
(This article belongs to the Special Issue BCR-ABL1 Negative Myeloproliferative Neoplasms)
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Review

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25 pages, 1397 KiB  
Review
Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies
by Vincenzo Nasillo, Giovanni Riva, Ambra Paolini, Fabio Forghieri, Luca Roncati, Beatrice Lusenti, Monica Maccaferri, Andrea Messerotti, Valeria Pioli, Andrea Gilioli, Francesca Bettelli, Davide Giusti, Patrizia Barozzi, Ivana Lagreca, Rossana Maffei, Roberto Marasca, Leonardo Potenza, Patrizia Comoli, Rossella Manfredini, Antonino Maiorana, Enrico Tagliafico, Mario Luppi and Tommaso Trentiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(4), 1906; https://doi.org/10.3390/ijms22041906 - 14 Feb 2021
Cited by 26 | Viewed by 6042
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue BCR-ABL1 Negative Myeloproliferative Neoplasms)
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22 pages, 2431 KiB  
Review
Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes
by Stefania Stella, Michele Massimino, Livia Manzella, Maria Stella Pennisi, Elena Tirrò, Chiara Romano, Silvia Rita Vitale, Adriana Puma, Cristina Tomarchio, Sandra Di Gregorio, Giuseppe Alberto Palumbo and Paolo Vigneri
Int. J. Mol. Sci. 2021, 22(2), 486; https://doi.org/10.3390/ijms22020486 - 6 Jan 2021
Cited by 11 | Viewed by 6814
Abstract
Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm3, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. HE may be associated with tissue or organ damage and, in this [...] Read more.
Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm3, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. HE may be associated with tissue or organ damage and, in this case, the disorder is classified as hypereosinophilic syndrome (HES). Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. With the advent of molecular genetic analyses, such as T-cell receptor gene rearrangement assays and Next Generation Sequencing, it is possible to better characterize these syndromes and establish which patients will benefit from pharmacological targeted therapy. In this review, we highlight the molecular alterations that are involved in the pathogenesis of eosinophil disorders and revise possible therapeutic approaches, either implemented in clinical practice or currently under investigation in clinical trials. Full article
(This article belongs to the Special Issue BCR-ABL1 Negative Myeloproliferative Neoplasms)
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17 pages, 2815 KiB  
Review
Atypical Chronic Myeloid Leukemia: Where Are We Now?
by Elena Crisà, Maura Nicolosi, Valentina Ferri, Chiara Favini, Gianluca Gaidano and Andrea Patriarca
Int. J. Mol. Sci. 2020, 21(18), 6862; https://doi.org/10.3390/ijms21186862 - 18 Sep 2020
Cited by 30 | Viewed by 7542
Abstract
Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real [...] Read more.
Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options. Full article
(This article belongs to the Special Issue BCR-ABL1 Negative Myeloproliferative Neoplasms)
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16 pages, 268 KiB  
Review
New Perspectives on Polycythemia Vera: From Diagnosis to Therapy
by Alessandra Iurlo, Daniele Cattaneo, Cristina Bucelli and Luca Baldini
Int. J. Mol. Sci. 2020, 21(16), 5805; https://doi.org/10.3390/ijms21165805 - 13 Aug 2020
Cited by 31 | Viewed by 8556
Abstract
Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 [...] Read more.
Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called “masked PV”, as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients’ prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors. Full article
(This article belongs to the Special Issue BCR-ABL1 Negative Myeloproliferative Neoplasms)
20 pages, 1964 KiB  
Review
Drug-Related Cutaneous Adverse Events in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Literature Review
by Alessandra Malato, Elena Rossi, Giuseppe Alberto Palumbo, Paola Guglielmelli and Novella Pugliese
Int. J. Mol. Sci. 2020, 21(11), 3900; https://doi.org/10.3390/ijms21113900 - 30 May 2020
Cited by 15 | Viewed by 4222
Abstract
Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk [...] Read more.
Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis. Full article
(This article belongs to the Special Issue BCR-ABL1 Negative Myeloproliferative Neoplasms)
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