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Cancers
Special Issues
Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms
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Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms

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

Deadline for manuscript submissions: 15 May 2024 | Viewed by 10648

Special Issue Editors

Dr. Jinming Song

E-Mail Website
Guest Editor
Department of Hematopathology and Lab Medicines, Moffitt Cancer Center, Tampa, FL 33612, USA
Interests: NextGen; myeloid neoplasm; mutations; myeloproliferative; myelodysplastic
Dr. Ling Zhang

E-Mail Website
Guest Editor
Department of Hematopatholology and Lab Medicines, Moffitt Cancer Center, Tampa, FL 33612, USA
Interests: myeloid neoplasms; histiocytic and histiocytic neoplasms; lymphomas; molecular diagnosis; targeted therapy
Dr. Andrew Kuykendall

E-Mail Website
Guest Editor
Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL 33612, USA
Interests: myelofibrosis; myeloproliferative neoplasm; polycythemia vera; essential thrombocythemia; JAK2 mutation; myelofibrosis; chronic neutrophilic leukemia

Special Issue Information

Dear Colleagues,

Myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and MPN NOS, are among the most common myeloid neoplasms. Their treatments and their prognosis are different. However, they can show overlapping clinical presentations and are sometimes difficult to distinguish from each other. Therefore, it is critical to perform correct diagnosis and stratification on patients with MPNs. With the advancement of new technologies such as NextGen sequencing, there has been rapid progress in the understanding about the pathogenesis, the diagnosis, the prognosis, and the targeted therapy of MPNs. The purpose of this Special Issue is to present the current advancements in the diagnosis and the prognosis prediction of MPNs. This Special Issue welcomes reviews as well as original research articles, which should be submitted by 15 May 2024.

Dr. Jinming Song
Dr. Ling Zhang
Dr. Andrew Kuykendall
Guest Editors

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

  • myeloproliferative neoplasm
  • chronic myeloid leukemia
  • polycythemia vera
  • essential thrombocythemia
  • primary myelofibrosis
  • MPN
  • CML
  • PMF
  • PV
  • ET

Published Papers (6 papers)

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Research

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18 pages, 2112 KiB  
Article
Reverse Transcription Can Critically Impact the Diagnostic Outcome of BCR::ABL1 Quantitative Real-Time RT-PCR
by Birgit Spiess, Helga Kleiner, Irina Tarnopolscaia, Nicole Naumann, Alice Fabarius, Wolf-Karsten Hofmann, Susanne Saussele and Wolfgang Seifarth
Cancers 2023, 15(15), 3914; https://doi.org/10.3390/cancers15153914 - 01 Aug 2023
Viewed by 1046
Abstract
Reverse transcriptases (RT) are essential tools in BCR::ABL1 fusion transcript monitoring in chronic myeloid leukemia (CML). The RT type and cDNA priming method may impair the stoichiometry of cDNA synthesis, thereby potentially introducing a bias in BCR::ABL1 qRT-PCR data. Using the Acrometrix™ BCR::ABL1 [...] Read more.
Reverse transcriptases (RT) are essential tools in BCR::ABL1 fusion transcript monitoring in chronic myeloid leukemia (CML). The RT type and cDNA priming method may impair the stoichiometry of cDNA synthesis, thereby potentially introducing a bias in BCR::ABL1 qRT-PCR data. Using the Acrometrix™ BCR::ABL1 reference panel and 37 clinical specimens, we have comparatively investigated the performance of the RTs MLV and SuperScript IV with random hexamer vs. target-specific priming. Quantitative RT-PCR results identified the priming type and RT type as major factors for diagnostic data variation, mainly due to the different efficacies of processing BCR::ABL1 low-copy-numbers (<50) compared to GUSB or ABL1 high-copy targets. The impairment of SuperScript IV in processing low- and high-copy-number RNA targets equally was not reflected by the diagnostically relevant Log (BCR::ABL1/GUSB%) values. Therefore, the correct representation of housekeeping and BCR::ABL1 target genes should have priority when aiming at as high a number of housekeeping gene copies as possible. Our data suggest that for improving BCR::ABL1 assay sensitivity, increased RNA/cDNA amounts and the use of distinct RT/priming combinations are advantageous. However, for inter-laboratory harmonization, the proper conversion factor according to the CML international standard (IS) has to be reevaluated each time the grade of RT is changed. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
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Review

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22 pages, 323 KiB  
Review
Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine
by Hammad Tashkandi and Ismail Elbaz Younes
Cancers 2024, 16(9), 1679; https://doi.org/10.3390/cancers16091679 - 26 Apr 2024
Viewed by 450
Abstract
Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of [...] Read more.
Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
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27 pages, 1922 KiB  
Review
Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements
by Tanvi Verma, Nikolaos Papadantonakis, Deniz Peker Barclift and Linsheng Zhang
Cancers 2024, 16(3), 514; https://doi.org/10.3390/cancers16030514 - 25 Jan 2024
Viewed by 2225
Abstract
Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation [...] Read more.
Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
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14 pages, 670 KiB  
Review
ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis
by Andrea Duminuco, Helen T. Chifotides, Sebastiano Giallongo, Cesarina Giallongo, Daniele Tibullo and Giuseppe A. Palumbo
Cancers 2024, 16(1), 154; https://doi.org/10.3390/cancers16010154 - 28 Dec 2023
Cited by 1 | Viewed by 1420
Abstract
Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin [...] Read more.
Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
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22 pages, 5862 KiB  
Review
Review and Updates on Systemic Mastocytosis and Related Entities
by Julie Y. Li, Christopher B. Ryder, Hailing Zhang, Samuel G. Cockey, Elizabeth Hyjek, Lynn C. Moscinski, Elizabeth Sagatys and Jinming Song
Cancers 2023, 15(23), 5626; https://doi.org/10.3390/cancers15235626 - 28 Nov 2023
Viewed by 1329
Abstract
Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by [...] Read more.
Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by KIT mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
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22 pages, 782 KiB  
Review
Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments
by Helen T. Chifotides, Srdan Verstovsek and Prithviraj Bose
Cancers 2023, 15(13), 3331; https://doi.org/10.3390/cancers15133331 - 24 Jun 2023
Cited by 4 | Viewed by 3236
Abstract
Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular [...] Read more.
Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum. Full article
(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)
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