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Cells
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Pathophysiology and Molecular Targets in Myeloid Neoplasia
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Pathophysiology and Molecular Targets in Myeloid Neoplasia

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

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 55365

Special Issue Editor

Dr. Florian H. Heidel

E-Mail Website
Guest Editor
Universitätsklinikum Jena und Medizinische Fakultät, Jena, Germany
Interests: stem cell aging; myeloid neoplasia

Special Issue Information

Dear Colleagues,

Myeloid cancers developing from the aging hematopoietic system share common genetic and epigenetic aberrations, irrespective of the clinical phenotype. While current treatment options are clearly focused on the disease phenotype and the underlying driver mutations, cancers within the myeloid spectrum rather represent a continuum of diseases. The underlying genetic and epigenetic landscape, comparable metabolic requirements, common functional dependencies, and shared interface with the immune system may facilitate the definition of pan-myeloid disease mechanisms and therapeutic targets. Identification of common pathophysiologic mechanisms may facilitate development of therapies to prevent progression or induce regression of the underlying clonal landscape. In this Special Issue, we aim to focus on commonalities and differences between preleukemic conditions and various blood cancers of the myeloid spectrum that may serve as therapeutic targets in the future. Contributions may therefore include primary research articles, reviews, as well as perspectives (if solicited by the editorial board).

Dr. Florian H. Heidel
Guest Editor

Manuscript Submission Information

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Keywords

  • stem cell aging
  • myeloid neoplasia
  • hematopoietic system

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Published Papers (8 papers)

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Review

23 pages, 1798 KiB  
Review
Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future
by Valentina R. Minciacchi, Rahul Kumar and Daniela S. Krause
Cells 2021, 10(1), 117; https://doi.org/10.3390/cells10010117 - 10 Jan 2021
Cited by 85 | Viewed by 14453
Abstract
Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here [...] Read more.
Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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26 pages, 3081 KiB  
Review
Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation
by Florian Perner and Scott A. Armstrong
Cells 2020, 9(12), 2721; https://doi.org/10.3390/cells9122721 - 21 Dec 2020
Cited by 13 | Viewed by 6014
Abstract
The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by [...] Read more.
The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by aberrant chromatin modifiers. Of note, a number of enzymatic inhibitors that block the catalytic function of histone modifying enzymes have been established and entered clinical trials. Unfortunately, many of these molecules do not have potent single-agent activity. One potential explanation for this phenomenon is the fact that those drugs do not profoundly disrupt the integrity of the aberrant network of multiprotein complexes on chromatin. Recent advances in drug development have led to the establishment of novel inhibitors of protein–protein interactions as well as targeted protein degraders that may provide inroads to longstanding effort to physically disrupt oncogenic multiprotein complexes on chromatin. In this review, we summarize some of the current concepts on the role epigenetic modifiers in malignant chromatin states with a specific focus on myeloid malignancies and recent advances in early-phase clinical trials. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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13 pages, 493 KiB  
Review
t(8;21) Acute Myeloid Leukemia as a Paradigm for the Understanding of Leukemogenesis at the Level of Gene Regulation and Chromatin Programming
by Sophie Kellaway, Paulynn S. Chin, Farnaz Barneh, Constanze Bonifer and Olaf Heidenreich
Cells 2020, 9(12), 2681; https://doi.org/10.3390/cells9122681 - 13 Dec 2020
Cited by 9 | Viewed by 4494
Abstract
Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription [...] Read more.
Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription factors, chromatin modifiers, DNA-methyltransferases, but also signaling molecules that activate inducible transcription factors controlling gene expression and cell growth. Mutant cells in AML patients are unable to differentiate and adopt new identities that are shaped by the original driver mutation and by rewiring their gene regulatory networks into regulatory phenotypes with enhanced fitness. One of the best-studied AML-subtypes is the t(8;21) AML which carries a translocation fusing sequences encoding the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO gene. The resulting oncoprotein, RUNX1/ETO has been studied for decades, both at the biochemical but also at the systems biology level. It functions as a dominant-negative version of RUNX1 and interferes with multiple cellular processes associated with myeloid differentiation, growth regulation and genome stability. In this review, we summarize our current knowledge of how this protein reprograms normal into malignant cells and how our current knowledge could be harnessed to treat the disease. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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18 pages, 1029 KiB  
Review
Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments
by Sebastian Scholl, Maximilian Fleischmann, Ulf Schnetzke and Florian H. Heidel
Cells 2020, 9(11), 2493; https://doi.org/10.3390/cells9112493 - 17 Nov 2020
Cited by 44 | Viewed by 7031
Abstract
Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of [...] Read more.
Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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32 pages, 4197 KiB  
Review
MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment
by Julian Grabek, Jasmin Straube, Megan Bywater and Steven W. Lane
Cells 2020, 9(8), 1901; https://doi.org/10.3390/cells9081901 - 14 Aug 2020
Cited by 28 | Viewed by 6158
Abstract
Myeloproliferative neoplasms (MPNs) constitute a group of disorders identified by an overproduction of cells derived from myeloid lineage. The majority of MPNs have an identifiable driver mutation responsible for cytokine-independent proliferative signalling. The acquisition of coexisting mutations in chromatin modifiers, spliceosome complex components, [...] Read more.
Myeloproliferative neoplasms (MPNs) constitute a group of disorders identified by an overproduction of cells derived from myeloid lineage. The majority of MPNs have an identifiable driver mutation responsible for cytokine-independent proliferative signalling. The acquisition of coexisting mutations in chromatin modifiers, spliceosome complex components, DNA methylation modifiers, tumour suppressors and transcriptional regulators have been identified as major pathways for disease progression and leukemic transformation. They also confer different sensitivities to therapeutic options. This review will explore the molecular basis of MPN pathogenesis and specifically examine the impact of coexisting mutations on disease biology and therapeutic options. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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20 pages, 1490 KiB  
Review
Therapeutic Target Discovery Using High-Throughput Genetic Screens in Acute Myeloid Leukemia
by Qiao Liu, Michelle Garcia, Shaoyuan Wang and Chun-Wei Chen
Cells 2020, 9(8), 1888; https://doi.org/10.3390/cells9081888 - 12 Aug 2020
Cited by 4 | Viewed by 4665
Abstract
The development of high-throughput gene manipulating tools such as short hairpin RNA (shRNA) and CRISPR/Cas9 libraries has enabled robust characterization of novel functional genes contributing to the pathological states of the diseases. In acute myeloid leukemia (AML), these genetic screen approaches have been [...] Read more.
The development of high-throughput gene manipulating tools such as short hairpin RNA (shRNA) and CRISPR/Cas9 libraries has enabled robust characterization of novel functional genes contributing to the pathological states of the diseases. In acute myeloid leukemia (AML), these genetic screen approaches have been used to identify effector genes with previously unknown roles in AML. These AML-related genes centralize alongside the cellular pathways mediating epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. The shRNA/CRISPR genetic screens also realized an array of candidate genes amenable to pharmaceutical targeting. This review aims to summarize genes, mechanisms, and potential therapeutic strategies found via high-throughput genetic screens in AML. We also discuss the potential of these findings to instruct novel AML therapies for combating drug resistance in this genetically heterogeneous disease. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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15 pages, 776 KiB  
Review
EZH2 in Myeloid Malignancies
by Jenny Rinke, Andrew Chase, Nicholas C. P. Cross, Andreas Hochhaus and Thomas Ernst
Cells 2020, 9(7), 1639; https://doi.org/10.3390/cells9071639 - 8 Jul 2020
Cited by 37 | Viewed by 6790
Abstract
Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for [...] Read more.
Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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33 pages, 1119 KiB  
Review
Immunotherapy in Myeloproliferative Diseases
by Lukas M. Braun and Robert Zeiser
Cells 2020, 9(6), 1559; https://doi.org/10.3390/cells9061559 - 26 Jun 2020
Cited by 15 | Viewed by 4929
Abstract
Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing [...] Read more.
Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing an effective anti-tumor immune response. MPNs are a potentially immunogenic disease as shown by their response to interferon-α treatment and allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Novel immunotherapeutic approaches such as immune checkpoint inhibition, tumor vaccination, or cellular therapies using target-specific lymphocytes have so far not shown strong therapeutic efficacy. Potential reasons could be the pro-inflammatory and immunosuppressive microenvironment in the bone marrow of patients with MPN, driving tumor immune escape. In this review, we discuss the biology of MPNs with respect to the pro-inflammatory milieu in the bone marrow (BM) and potential immunotherapeutic approaches. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Targets in Myeloid Neoplasia)
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