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Cancers
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New Approaches to Biology and Treatment of Acute Leukemia
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New Approaches to Biology and Treatment of Acute Leukemia

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

Deadline for manuscript submissions: 25 August 2024 | Viewed by 6661

Special Issue Editors

Dr. Régis Thierry Costello

E-Mail Website
Guest Editor
Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Marseille, France
Interests: acute leukemia; tumor escape; natural killer cells; chemotherapy; single cell analysis; CRISPR cas9
Dr. Laure Farnault

E-Mail Website
Guest Editor
Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Marseille, France
Interests: acute leukemia

Special Issue Information

Dear Colleagues,

Progress in onco-hematology has never been as rapid as it is today. In particular, new technologies, especially in high-throughput molecular biology, allow us to better understand the characteristics of acute leukemias. Above all, biological data are becoming theranostic, since they allow us to adapt our treatment to each patient, and to each leukemia, for increasingly targeted and individualized treat-ments. For example, the detection of mutations such as IDH1, IDH2 or FLT3 leads to specific treatments that significantly improve response rates, duration of response and ultimately overall survival. These advances have led, among other things, to new classifications of acute leukemias, which modify our therapeutic attitudes. All these elements make it necessary to update our biological and therapeutic approaches to acute leukemias while evaluating the potential contribution of new analysis technologies, such as single-cell techniques, in order to better determine a therapeutic strategy combining classical chemotherapy, immunotherapy and targeted therapies.

Dr. Régis Thierry Costello
Dr. Laure Farnault
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

  • acute leukemia
  • targeted therapy
  • single-cell analysis
  • theranostic
  • high-throughput molecular biology

Published Papers (5 papers)

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Research

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23 pages, 3657 KiB  
Article
PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia
by Caio Bezerra Machado, Emerson Lucena da Silva, Wallax Augusto Silva Ferreira, Flávia Melo Cunha de Pinho Pessoa, Andreza Urba de Quadros, Daianne Maciely Carvalho Fantacini, Izadora Peter Furtado, Rafaela Rossetti, Roberta Maraninchi Silveira, Sarah Caroline Gomes de Lima, Fernando Augusto Rodrigues Mello Júnior, Aline Damasceno Seabra, Edith Cibelle de Oliveira Moreira, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, Raquel Carvalho Montenegro, Rodrigo Monteiro Ribeiro, André Salim Khayat, Rommel Mário Rodriguez Burbano, Edivaldo Herculano Correa de Oliveira, Dimas Tadeu Covas, Lucas Eduardo Botelho de Souza and Caroline de Fátima Aquino Moreira-Nunesadd Show full author list remove Hide full author list
Cancers 2023, 15(23), 5510; https://doi.org/10.3390/cancers15235510 - 22 Nov 2023
Viewed by 914
Abstract
Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated [...] Read more.
Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice. Full article
(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)
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16 pages, 3315 KiB  
Article
Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape
by Roshani Sinha, Mai Dvorak, Ananthakrishnan Ganesan, Larry Kalesinskas, Charlotte M. Niemeyer, Christian Flotho, Kathleen M. Sakamoto, Norman Lacayo, Rachana Vinay Patil, Rhonda Perriman, Alma-Martina Cepika, Yunying Lucy Liu, Alex Kuo, Paul J. Utz, Purvesh Khatri and Alice Bertaina
Cancers 2023, 15(21), 5204; https://doi.org/10.3390/cancers15215204 - 29 Oct 2023
Viewed by 1175
Abstract
Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by RAS pathway mutations, of which >35% are gain-of-function in PTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not [...] Read more.
Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by RAS pathway mutations, of which >35% are gain-of-function in PTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not been explored. Using global mass cytometry, Epigenetic Time of Flight (EpiTOF), we analyzed hematopoietic stem and progenitor cells (HSPCs) from five JMML patients with PTPN11 mutations. These data revealed statistically significant changes in histone methylation, phosphorylation, and acetylation marks that were unique to JMML HSPCs when compared with healthy controls. Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML. Full article
(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)
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16 pages, 2866 KiB  
Article
MicroRNA Expression Patterns Reveal a Role of the TGF-β Family Signaling in AML Chemo-Resistance
by Paula Reichelt, Stephan Bernhart, Franziska Wilke, Sebastian Schwind, Michael Cross, Uwe Platzbecker and Gerhard Behre
Cancers 2023, 15(20), 5086; https://doi.org/10.3390/cancers15205086 - 21 Oct 2023
Viewed by 1132
Abstract
Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in [...] Read more.
Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in translation, which are known to play a role in chemo-resistance. To address this, we compared miRNA profiles in paired chemo-sensitive and chemo-resistant subclones of HL60 cells and used a bioinformatics approach to predict affected pathways. From a total of 38 KEGG pathways implicated, TGF-β/activin family signaling was selected for further study. Chemo-resistant HL60 cells showed an increased TGF-β response but were not rendered chemo-sensitive by specific inhibitors. Differential pathway expression in primary AML samples was then investigated at the RNA level using publically available gene expression data in the TGCA database and by longitudinal analysis of pre- and post-resistance samples available from a limited number of patients. This confirmed differential expression and activity of the TGF-β family signaling pathway upon relapse and revealed that the expression of TGF-β and activin signaling genes at diagnosis was associated with overall survival. Our focus on a matched pair of cytarabine sensitive and resistant sublines to identify miRNAs that are associated specifically with resistance, coupled with the use of pathway analysis to rank predicted targets, has thus identified the activin/TGF-β signaling cascade as a potential target for overcoming resistance in AML. Full article
(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)
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Review

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13 pages, 267 KiB  
Review
New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches
by Jaime L. Roman Diaz, Mariola Vazquez Martinez and Farhad Khimani
Cancers 2024, 16(3), 677; https://doi.org/10.3390/cancers16030677 - 05 Feb 2024
Viewed by 1498
Abstract
Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily [...] Read more.
Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease. Full article
(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)
11 pages, 482 KiB  
Review
Impact of Next-Generation Sequencing in Diagnosis, Prognosis and Therapeutic Management of Acute Myeloid Leukemia/Myelodysplastic Neoplasms
by Lamia Madaci, Laure Farnault, Norman Abbou, Jean Gabert, Geoffroy Venton and Régis Costello
Cancers 2023, 15(13), 3280; https://doi.org/10.3390/cancers15133280 - 22 Jun 2023
Cited by 2 | Viewed by 1324
Abstract
For decades, the diagnosis, prognosis and thus, the treatment of acute myeloblastic leukemias and myelodysplastic neoplasms has been mainly based on morphological aspects, as evidenced by the French-American-British classification. The morphological aspects correspond quite well, in a certain number of particular cases, to [...] Read more.
For decades, the diagnosis, prognosis and thus, the treatment of acute myeloblastic leukemias and myelodysplastic neoplasms has been mainly based on morphological aspects, as evidenced by the French-American-British classification. The morphological aspects correspond quite well, in a certain number of particular cases, to particular evolutionary properties, such as acute myelomonoblastic leukemias with eosinophils or acute promyelocytic leukemias. Advances in biology, particularly “classical” cytogenetics (karyotype) and molecular cytogenetics (in situ hybridization), have made it possible to associate certain morphological features with particular molecular abnormalities, such as the pericentric inversion of chromosome 16 and translocation t(15;17) in the two preceding examples. Polymerase chain reaction techniques have made it possible to go further in these analyses by associating these karyotype abnormalities with their molecular causes, CBFbeta fusion with MYH11 and PML-RAR fusion in the previous cases. In these two examples, the molecular abnormality allows us to better define the pathophysiology of leukemia, to adapt certain treatments (all-transretinoic acid, for example), and to follow up the residual disease of strong prognostic value beyond the simple threshold of less than 5% of marrow blasts, signaling the complete remission. However, the new sequencing techniques of the next generation open up broader perspectives by being able to analyze several dozens of molecular abnormalities, improving all levels of management, from diagnosis to prognosis and treatment, even if it means that morphological aspects are increasingly relegated to the background. Full article
(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)
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