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Novel Agents and Mechanisms in Acute Leukemias
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Novel Agents and Mechanisms in Acute Leukemias

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 26622

Special Issue Editors

Dr. Giovanni Martinelli

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Guest Editor
Department of Hematology and Sciences Oncology, Institute of Haematology "L. and A. Seràgnoli" S. Orsola, University of Bologna, 40126 Bologna, Italy
Interests: leukemias; lymphomas; acute leukemia; chronic myeloid leukemia
Special Issues, Collections and Topics in MDPI journals
Dr. Claudio Cerchione

E-Mail Website
Guest Editor
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, 47014 Meldola, Italy
Interests: acute lymphoblastic leukemia; acute myeloid leukemia; myelodysplastic syndromes; multiple myeloma and MGUS; non-Hodgkin and Hodgkin lymphoma
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Naval Daver

E-Mail Website
Guest Editor
Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); bone marrow aspiration; bone marrow transplant
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The last 4–5 years have ushered in a new era in acute myeloid leukemia therapy, with the advent and approval of multiple targeted therapies. Additionally, an improved understanding of the immune system in patients with hematologic malignancies has resulted in major progress in the development of immune therapies for the treatment of patients with AML, including monoclonal antibodies with or without conjugated toxins (bacterial or chemical), bispecific T-cell engagers and DART antibodies, immune-checkpoint-based therapies, and CAR-T cell approaches.

At the same time, there is an increasing understanding of AML tumor biology, creating the rationale for new combinations of drugs and new therapy development.

The numerous ongoing trials evaluating these novel therapies, with well-designed correlative interrogations of the immune system in patients treated in such trials, will further enhance our understanding of immune therapies as single-agent and combination approaches for the treatment of AML.

This Special Issue aims to focus on novel agents and their combinations. Focus will be placed on the efficacy of novel therapeutics and promising combination approaches to further improve outcomes in the treatment of patients with AML. We welcome the submission of original research articles and reviews.

Prof. Dr. Giovanni Martinelli
Dr. Claudio Cerchione
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • novel agents
  • target therapy

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Published Papers (5 papers)

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Research

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16 pages, 3351 KiB  
Article
Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia
by Anna Richter, Elisabeth Fischer, Clemens Holz, Julia Schulze, Sandra Lange, Anett Sekora, Gudrun Knuebel, Larissa Henze, Catrin Roolf, Hugo Murua Escobar and Christian Junghanss
Int. J. Mol. Sci. 2021, 22(5), 2771; https://doi.org/10.3390/ijms22052771 - 9 Mar 2021
Cited by 8 | Viewed by 3363
Abstract
Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 [...] Read more.
Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL. Full article
(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias)
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22 pages, 5601 KiB  
Article
Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib
by Sina Sender, Anett Sekora, Simon Villa Perez, Oleksandra Chabanovska, Annegret Becker, Anaclet Ngezahayo, Christian Junghanss and Hugo Murua Escobar
Int. J. Mol. Sci. 2021, 22(2), 592; https://doi.org/10.3390/ijms22020592 - 8 Jan 2021
Cited by 2 | Viewed by 3549
Abstract
Background: Impaired B-cell receptor (BCR) function has been associated with the progress of several B-cell malignancies. The spleen tyrosine kinase (SYK) represents a potential therapeutic target in a subset of B-cell neoplasias. In precursor B-acute lymphoblastic leukemia (B-ALL), the pathogenic role and therapeutic [...] Read more.
Background: Impaired B-cell receptor (BCR) function has been associated with the progress of several B-cell malignancies. The spleen tyrosine kinase (SYK) represents a potential therapeutic target in a subset of B-cell neoplasias. In precursor B-acute lymphoblastic leukemia (B-ALL), the pathogenic role and therapeutic potential of SYK is still controversially discussed. We evaluate the application of the SYK inhibitor entospletinib (Ento) in pre- and pro-B-ALL cell lines, characterizing the biologic and molecular effects. Methods: SYK expression was characterized in pre-B-ALL (NALM-6) and pro-B-ALL cell lines (SEM and RS4;11). The cell lines were exposed to different Ento concentrations and the cell biological response analyzed by proliferation, metabolic activity, apoptosis induction, cell-cycle distribution and morphology. BCR pathway gene expression and protein modulations were further characterized. Results: Ento significantly induced anti-proliferative and pro-apoptotic effects in NALM-6 and SEM, while barely affecting RS4;11. Targeted RNAseq revealed pronounced gene expression modulation only in NALM-6, while Western Blot analyses demonstrated that vital downstream effector proteins, such as pAKT, pERK, pGSK3β, p53 and BCL-6, were affected by Ento exposure in the inhibitor-sensitive cell lines. Conclusion: Different acting modes of Ento, independent of pre-BCR dependency, were characterized, unexpected in SEM. Accordingly, SYK classifies as a potential target structure in a subset of pro-B-ALLs. Full article
(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias)
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13 pages, 1540 KiB  
Article
Phenolic Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells
by Miguel Olivas-Aguirre, Liliana Torres-López, Igor Pottosin and Oxana Dobrovinskaya
Int. J. Mol. Sci. 2021, 22(1), 204; https://doi.org/10.3390/ijms22010204 - 28 Dec 2020
Cited by 38 | Viewed by 4077
Abstract
Anticancer activity of different phenols is documented, but underlying mechanisms remain elusive. Recently, we have shown that cannabidiol kills the cells of acute lymphoblastic leukemia (ALL) by a direct interaction with mitochondria, with their consequent dysfunction. In the present study, cytotoxic effects of [...] Read more.
Anticancer activity of different phenols is documented, but underlying mechanisms remain elusive. Recently, we have shown that cannabidiol kills the cells of acute lymphoblastic leukemia (ALL) by a direct interaction with mitochondria, with their consequent dysfunction. In the present study, cytotoxic effects of several phenolic compounds against human the T-ALL cell line Jurkat were tested by means of resazurin-based metabolic assay. To unravel underlying mechanisms, mitochondrial membrane potential (∆Ψm) and [Ca2+]m measurements were undertaken, and reactive oxygen species generation and cell death were evaluated by flow cytometry. Three out of eight tested phenolics, cannabidiol, curcumin and quercetin, which displayed a significant cytotoxic effect, also dissipated the ∆Ψm and induced a significant [Ca2+]m increase, whereas inefficient phenols did not. Dissipation of the ∆Ψm by cannabidiol was prevented by cyclosporine A and reverted by Ru360, inhibitors of the permeation transition pore and mitochondrial Ca2+ uniporter, respectively. Ru360 prevented the phenol-induced [Ca2+]m rise, but neither cyclosporine A nor Ru360 affected the curcumin- and quercetin-induced ∆Ψm depolarization. Ru360 impeded the curcumin- and cannabidiol-induced cell death. Thus, all three phenols exert their antileukemic activity via mitochondrial Ca2+ overload, whereas curcumin and quercetin suppress the metabolism of leukemic cells by direct mitochondrial uncoupling. Full article
(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias)
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Review

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31 pages, 1663 KiB  
Review
New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy
by Fabio Andreozzi, Fulvio Massaro, Sebastian Wittnebel, Chloé Spilleboudt, Philippe Lewalle and Adriano Salaroli
Int. J. Mol. Sci. 2022, 23(7), 3887; https://doi.org/10.3390/ijms23073887 - 31 Mar 2022
Cited by 15 | Viewed by 5000
Abstract
For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several [...] Read more.
For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML. Full article
(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias)
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17 pages, 562 KiB  
Review
A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia
by Massimo Martino, Caterina Alati, Filippo Antonio Canale, Gerardo Musuraca, Giovanni Martinelli and Claudio Cerchione
Int. J. Mol. Sci. 2021, 22(4), 2150; https://doi.org/10.3390/ijms22042150 - 21 Feb 2021
Cited by 70 | Viewed by 9530
Abstract
Introduction: Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients. Areas [...] Read more.
Introduction: Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients. Areas covered: Efficacy and safety of CAR-T therapy in R/R B-ALL patients. Expert opinion: CD19 CAR-T infusion induce high CR rates in patients with poor prognosis and few therapeutic options, while real-life data demonstrate similar results with an interestingly lower incidence of grade 3/4 toxicity. Nevertheless, despite impressive in-depth responses, more than half of patients will experience a relapse. Therefore, rather than using CAR-T cell therapy as a stand-alone option, consolidation with allogeneic stem-cell transplant (Allo-SCT) after CAR-T treatment might increase long-term outcome. Moreover, CD19 is one target, but several other targets are being examined, such as CD20 and CD22 and dual-targeting CARs or combination therapy. Another issue is the time consuming process of CAR-T engineering. New platforms have shortened the CAR-T cell manufacturing process, and studies are underway to evaluate the effectiveness. Another way to mitigate waiting is the development of allogeneic “off the shelf” therapy. In conclusion, CD19-targeted CAR-modified T-cell therapy has shown unprecedented results in patients without curative options. Future work focusing on target identification, toxicity management and reducing manufacturing time will broaden the clinical applicability and bring this exciting therapy to more patients, with longer-term remissions without additional Allo-SCT. Full article
(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias)
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