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Molecular and Cellular Mechanisms of Cancers: Acute Leukemia

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Keywords
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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 June 2020) | Viewed by 29768

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Special Issue Editor

Prof. Dr. Øystein Bruserud

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Guest Editor

Department of Medicine, Helse Bergen Haukeland University Hospital, 5020 Bergen, Norway
Interests: myeloid leukemia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will focus on the leukemia cell biology in acute myeloid leukemia (AML), including the acute promyelocytic leukemia (APL) variant of AML and acute lymphoblastic leukemia (ALL).

Decades of research have led to the accumulation of substantial knowledge about the biology of AML. It is a stem cell-driven malignancy, and the interactions between AML stem cells and the leukemia-supporting cells in the bone marrow stem cell niche marrow have been extensively characterized. A number of recurrent molecular and genetic aberrations have been detected and established as drivers and important prognosticators of AML. Despite these advances, the outcome for patients with AML remains poor.

APL is a disease with high long-term, leukemia-free survival, but it requires immediate therapeutic interventions if the diagnosis is suspected to reduce the risk of severe early complications and early mortality. Even though new and highly effective therapeutic strategies have been developed during the last decade, early mortality is still a therapeutic challenge.

ALL is also a heterogeneous group of hematologic malignancies characterized by the proliferation of immature lymphoid progenitors in various lymphoid organs, i.e., bone marrow, peripheral blood, and extramedullary sites. The treatment of this disease is evolving very rapidly, due to our increased understanding of its heterogeneity and complexity. This increased knowledge has contributed to the development of several new therapeutic strategies, especially various forms of immunotherapy and molecular targeting.

This Special Issue welcomes both original papers and review articles addressing all aspects of acute leukemia cell biology, including the following:

The molecular mechanisms and the functional cellular alterations involved in the development of secondary acute leukemia from preleukemic diseases or following chemotherapy;
The role of intracellular signaling in the regulation of leukemia cell proliferation, survival, and metabolism;
The communication between leukemic cells and neighboring cells through direct contact or the release of soluble mediators into the common microenvironment;
The therapeutic targeting of intracellular molecular mechanisms or the extracellular communication with neighboring cells;
Single cell analyses as a diagnostic tool in acute leukemia, e.g., the detection of minimal residual disease or clonal heterogeneity.

Prof. Øystein Bruserud
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

acute myeloid leukemia
acute lymphoblastic leukemia
acute promyelocytic leukemia
leukemogenesis
clonal heterogeneity
targeted therapy
intracellular signaling pathways
bone marrow microenvironment
cellular communication
chemosensitivity
minimal residual disease

Published Papers (5 papers)

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Research

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19 pages, 3617 KiB

Open AccessArticle

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

by Håkon Reikvam

Cells 2020, 9(7), 1677; https://doi.org/10.3390/cells9071677 - 12 Jul 2020

Cited by 10 | Viewed by 2465

Abstract

Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Acute Leukemia)

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26 pages, 5742 KiB

Open AccessFeature PaperArticle

Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

by Ida Sofie Grønningsæter, Håkon Reikvam, Elise Aasebø, Sushma Bartaula-Brevik, Tor Henrik Tvedt, Øystein Bruserud and Kimberley Joanne Hatfield

Cells 2020, 9(5), 1155; https://doi.org/10.3390/cells9051155 - 07 May 2020

Cited by 26 | Viewed by 3937

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer resulting in accumulation of immature, dysfunctional blood cells in the bone marrow. Changes in cell metabolism are features of many cancers, including AML and this may be exploited as a therapeutic target. In this study we investigated the in vitro antileukemic effects of seven metabolic inhibitors that target different metabolic pathways. The metabolic inhibitors were tested on AML cells derived from 81 patients using proliferation and viability assays; we also compared global gene expression and proteomic profiles for various patient subsets. Metformin, 2DG, 6AN, BPTES and ST1326 had strong antiproliferative and proapoptotic effects for most patients, whereas lonidamine and AZD3965 had an effect only for a minority. Antiproliferative effects on AML cells were additive when combined with the chemotherapeutic agent AraC. Using unsupervised hierarchical clustering, we identified a strong antiproliferative effect on AML cells after treatment with metabolic inhibitors for a subset of 29 patients. Gene expression and proteomic studies suggested that this subset was characterized by altered metabolic and transcriptional regulation. In addition, the Bcl-2 inhibitor venetoclax, in combination with 2DG or 6AN, increased the antiproliferative effects of these metabolic inhibitors on AML cells. Therapeutic targeting of cellular metabolism may have potential in AML, but the optimal strategy will likely differ between patients. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Acute Leukemia)

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16 pages, 2512 KiB

Open AccessArticle

ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia

by Adrián Montaño, Jose Luis Ordoñez, Verónica Alonso-Pérez, Jesús Hernández-Sánchez, Sandra Santos, Teresa González, Rocío Benito, Ignacio García-Tuñón and Jesús María Hernández-Rivas

Cells 2020, 9(1), 215; https://doi.org/10.3390/cells9010215 - 15 Jan 2020

Cited by 15 | Viewed by 4261

Abstract

Background: The t(12;21)(p13;q22), which fuses ETV6 and RUNX1 genes, is the most common genetic abnormality in children with B-cell precursor acute lymphoblastic leukaemia. The implication of the fusion protein in leukemogenesis seems to be clear. However, its role in the maintenance of the disease continues to be controversial. Methods: Generation of an in vitro ETV6/RUNX1 knock out model using the CRISPR/Cas9 gene editing system. Functional characterization by RNA sequencing, proliferation assays, apoptosis and pharmacologic studies, and generation of edited-cell xenograft model. Results: The expression of ETV6/RUNX1 fusion gene was completely eliminated, thus generating a powerful model on which to study the role of the fusion gene in leukemic cells. The loss of fusion gene expression led to the deregulation of biological processes affecting survival such as apoptosis resistance and cell proliferation capacity. Tumour cells showed higher levels of apoptosis, lower proliferation rate and a greater sensitivity to PI3K inhibitors in vitro along as a decrease in tumour growth in xenografts models after ETV6/RUNX1 fusion gene abrogation. Conclusions: ETV6/RUNX1 fusion protein seems to play an important role in the maintenance of the leukemic phenotype and could thus become a potential therapeutic target. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Acute Leukemia)

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Review

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20 pages, 998 KiB

Open AccessReview

Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

by Jan Philipp Bewersdorf and Amer M. Zeidan

Cells 2020, 9(10), 2310; https://doi.org/10.3390/cells9102310 - 17 Oct 2020

Cited by 35 | Viewed by 12474

Abstract

Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred to as hyperleukocytosis. Hyperleukocytosis has been associated with an adverse prognosis and a higher incidence of life-threatening complications such as leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The molecular processes underlying hyperleukocytosis have not been fully elucidated yet. However, the interactions between leukemic blasts and endothelial cells leading to leukostasis and DIC as well as the processes in the bone marrow microenvironment leading to the massive entry of leukemic blasts into the peripheral blood are becoming increasingly understood. Leukemic blasts interact with endothelial cells via cell adhesion molecules such as various members of the selectin family which are upregulated via inflammatory cytokines released by leukemic blasts. Besides their role in the development of leukostasis, cell adhesion molecules have also been implicated in leukemic stem cell survival and chemotherapy resistance and can be therapeutically targeted with specific inhibitors such as plerixafor or GMI-1271 (uproleselan). However, in the absence of approved targeted therapies supportive treatment with the uric acid lowering agents allopurinol and rasburicase as well as aggressive intravenous fluid hydration for the treatment and prophylaxis of TLS, transfusion of blood products for the management of DIC, and cytoreduction with intensive chemotherapy, leukapheresis, or hydroxyurea remain the mainstay of therapy for AML patients with hyperleukocytosis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Acute Leukemia)

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20 pages, 756 KiB

Open AccessReview

Targeting Metabolic Reprogramming in Acute Myeloid Leukemia

by Isabel Castro, Belém Sampaio-Marques and Paula Ludovico

Cells 2019, 8(9), 967; https://doi.org/10.3390/cells8090967 - 24 Aug 2019

Cited by 45 | Viewed by 5893

Abstract

The cancer metabolic reprogramming allows the maintenance of tumor proliferation, expansion and survival by altering key bioenergetics, biosynthetic and redox functions to meet the higher demands of tumor cells. In addition, several metabolites are also needed to perform signaling functions that further promote tumor growth and progression. These metabolic alterations have been exploited in different cancers, including acute myeloid leukemia, as novel therapeutic strategies both in preclinical models and clinical trials. Here, we review the complexity of acute myeloid leukemia (AML) metabolism and discuss how therapies targeting different aspects of cellular metabolism have demonstrated efficacy and how they provide a therapeutic window that should be explored to target the metabolic requirements of AML cells. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Acute Leukemia)

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