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Molecular Research on Acute Lymphoblastic Leukemia 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (10 November 2022) | Viewed by 15283

Special Issue Editor

CNR Istituto di Genetica Molecolare, Unità di Bologna, 40136 Bologna, Italy
Interests: cancer signaling in myelodysplastic syndromes, acute leukemias, and bone and soft tissue sarcomas; function of nuclear lamins: molecular interactions between lamins and the nuclear lamina components in musculoskeletal tumors (osteosarcoma and Ewing sarcoma)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue "Molecular Research on Acute Lymphoblastic Leukemia" (https://www.mdpi.com/journal/ijms/special_issues/ALL).

ALL is a heterogeneous group of hematologic malignancies characterized by the impaired differentiation and proliferation of immature lymphoid progenitors in bone marrow, peripheral blood, and extramedullary sites. Treatment of ALL is evolving very rapidly, due to increased understanding of the genetic heterogeneity and complexity of ALL, which has contributed to the development of novel immunotherapies and targeted therapy strategies.

Among immunotherapeutic approaches, cell surface antigens can be targeted with several different approaches, including monoclonal antibodies, antibody–drug conjugates (ADC), bispecific T cell engaging (BiTE) antibodies, and chimeric antigen receptor (CAR) T cells.

While immunotherapeutic avenues are playing a central role in the field of B-ALL, new molecular therapies are being evaluated in Philadelphia chromosome-positive (Ph+) ALL, Philadelphia-like (Ph-like) ALL, and T-ALL, with a challenge due to a wide variety of disease and patient-specific factors, such as the coexistence of multiple driver mutations, and interconnected signal transduction pathways.

This Special Issue of the International Journal of Molecular Sciences will focus on "Molecular Research on Acute Lymphoblastic Leukemia 2.0”, providing an overview of the new targeted therapeutic approaches in ALL and will also discuss how new technologies, such as next-generation sequencing, proteomics, metabolomics, and computational analysis should provide a deeper insight into active signaling networks to identify critical signaling hubs, novel potential druggable targets and new clinical care strategies, taking into account individual variability in the environment, genetics, and molecular phenotype.

Dr. Francesca Chiarini
Guest Editor

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Keywords

  • Acute Lymphoblastic Leukemia
  • PI3K/AKT/mTOR
  • Targeted Therapy
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Tumor Microenvironment

Published Papers (6 papers)

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Research

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19 pages, 6574 KiB  
Article
Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling
by Huideng Long, Yue Hou, Jun Li, Chunhua Song and Zheng Ge
Int. J. Mol. Sci. 2023, 24(7), 6816; https://doi.org/10.3390/ijms24076816 - 06 Apr 2023
Cited by 5 | Viewed by 1786
Abstract
Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 [...] Read more.
Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
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10 pages, 296 KiB  
Article
Influence of Genetic Variations in miRNA and Genes Encoding Proteins in the miRNA Synthesis Complex on Toxicity of the Treatment of Pediatric B-Cell ALL in the Brazilian Amazon
by Elisa da Silva Menezes, Francisco Cezar Aquino de Moraes, Amanda de Nazaré Cohen-Paes, Alayde Vieira Wanderley, Esdras Edgar Batista Pereira, Lucas Favacho Pastana, Antônio André Conde Modesto, Paulo Pimentel de Assumpção, Rommel Mario Rodríguez Burbano, Sidney Emanuel Batista dos Santos, Ney Pereira Carneiro dos Santos and Marianne Rodrigues Fernandes
Int. J. Mol. Sci. 2023, 24(5), 4431; https://doi.org/10.3390/ijms24054431 - 23 Feb 2023
Cited by 1 | Viewed by 1406
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Single nucleotide variants (SNVs) in miRNA and genes encoding proteins of the miRNA synthesis complex (SC) may affect the processing of drugs used in the treatment of ALL, resulting in [...] Read more.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Single nucleotide variants (SNVs) in miRNA and genes encoding proteins of the miRNA synthesis complex (SC) may affect the processing of drugs used in the treatment of ALL, resulting in treatment-related toxicities (TRTs). We investigated the role of 25 SNVs in microRNA genes and genes encoding proteins of the miRNA SC, in 77 patients treated for ALL-B from the Brazilian Amazon. The 25 SNVs were investigated using the TaqMan® OpenArray™ Genotyping System. SNVs rs2292832 (MIR149), rs2043556 (MIR605), and rs10505168 (MIR2053) were associated with an increased risk of developing Neurological Toxicity, while rs2505901 (MIR938) was associated with protection from this toxicity. MIR2053 (rs10505168) and MIR323B (rs56103835) were associated with protection from gastrointestinal toxicity, while DROSHA (rs639174) increased the risk of development. The rs2043556 (MIR605) variant was related to protection from infectious toxicity. SNVs rs12904 (MIR200C), rs3746444 (MIR499A), and rs10739971 (MIRLET7A1) were associated with a lower risk for severe hematologic toxicity during ALL treatment. These findings reveal the potential for the use of these genetic variants to understand the development of toxicities related to the treatment of ALL in patients from the Brazilian Amazon region. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
11 pages, 5928 KiB  
Article
Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells
by Mohammed Razeeth Shait Mohammed, Faisal Alzahrani, Salman Hosawi, Hani Choudhry and Mohammad Imran Khan
Int. J. Mol. Sci. 2022, 23(12), 6653; https://doi.org/10.3390/ijms23126653 - 15 Jun 2022
Cited by 2 | Viewed by 2184
Abstract
Leukemia is one of the most common primary malignancies of the hematologic system in both children and adults and remains a largely incurable or relapsing disease. The elucidation of disease subtypes based on mutational profiling has not improved clinical outcomes. IDH1/2 are critical [...] Read more.
Leukemia is one of the most common primary malignancies of the hematologic system in both children and adults and remains a largely incurable or relapsing disease. The elucidation of disease subtypes based on mutational profiling has not improved clinical outcomes. IDH1/2 are critical enzymes of the TCA cycle that produces α-ketoglutarate (αKG). However, their mutated version is well reported in various cancer types, including leukemia, which produces D-2 hydroxyglutarate (D-2HG), an oncometabolite. Recently, some studies have shown that wild-type IDH1 is highly expressed in non-small cell lung carcinoma (NSCLC), primary glioblastomas (GBM), and several hematological malignancies and is correlated with disease progression. This work shows that the treatment of wild-type IDH1 leukemia cells with a specific IDH1 inhibitor shifted leukemic cells toward glycolysis from the oxidative phosphorylation (OXPHOS) phenotype. We also noticed a reduction in αKG in treated cells, possibly suggesting the inhibition of IDH1 enzymatic activity. Furthermore, we found that IDH1 inhibition reduced the metabolites related to one-carbon metabolism, which is essential for maintaining global methylation in leukemic cells. Finally, we observed that metabolic alteration in IDH1 inhibitor-treated leukemic cells promoted reactive oxygen species (ROS) formation and the loss of mitochondrial membrane potential, leading to apoptosis in leukemic cells. We showed that targeting wild-type IDH1 leukemic cells promotes metabolic alterations that can be exploited for combination therapies for a better outcome. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
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17 pages, 1634 KiB  
Article
Multi-Cohort Transcriptomic Subtyping of B-Cell Acute Lymphoblastic Leukemia
by Ville-Petteri Mäkinen, Jacqueline Rehn, James Breen, David Yeung and Deborah L. White
Int. J. Mol. Sci. 2022, 23(9), 4574; https://doi.org/10.3390/ijms23094574 - 20 Apr 2022
Cited by 8 | Viewed by 2818
Abstract
RNA sequencing provides a snapshot of the functional consequences of genomic lesions that drive acute lymphoblastic leukemia (ALL). The aims of this study were to elucidate diagnostic associations (via machine learning) between mRNA-seq profiles, independently verify ALL lesions and develop easy-to-interpret transcriptome-wide biomarkers [...] Read more.
RNA sequencing provides a snapshot of the functional consequences of genomic lesions that drive acute lymphoblastic leukemia (ALL). The aims of this study were to elucidate diagnostic associations (via machine learning) between mRNA-seq profiles, independently verify ALL lesions and develop easy-to-interpret transcriptome-wide biomarkers for ALL subtyping in the clinical setting. A training dataset of 1279 ALL patients from six North American cohorts was used for developing machine learning models. Results were validated in 767 patients from Australia with a quality control dataset across 31 tissues from 1160 non-ALL donors. A novel batch correction method was introduced and applied to adjust for cohort differences. Out of 18,503 genes with usable expression, 11,830 (64%) were confounded by cohort effects and excluded. Six ALL subtypes (ETV6::RUNX1, KMT2A, DUX4, PAX5 P80R, TCF3::PBX1, ZNF384) that covered 32% of patients were robustly detected by mRNA-seq (positive predictive value ≥ 87%). Five other frequent subtypes (CRLF2, hypodiploid, hyperdiploid, PAX5 alterations and Ph-positive) were distinguishable in 40% of patients at lower accuracy (52% ≤ positive predictive value ≤ 73%). Based on these findings, we introduce the Allspice R package to predict ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Two examples of Allspice applied to previously unseen ALL patient samples with atypical lesions are included. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
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18 pages, 2020 KiB  
Article
Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy
by Alexandra Semchenkova, Ekaterina Mikhailova, Alexander Komkov, Marina Gaskova, Ruslan Abasov, Evgenii Matveev, Marat Kazanov, Ilgar Mamedov, Anna Shmitko, Vera Belova, Anna Miroshnichenkova, Olga Illarionova, Yulia Olshanskaya, Grigory Tsaur, Tatiana Verzhbitskaya, Natalia Ponomareva, Gleb Bronin, Konstantin Kondratchik, Larisa Fechina, Yulia Diakonova, Liudmila Vavilova, Natalia Myakova, Galina Novichkova, Alexey Maschan, Michael Maschan, Elena Zerkalenkova and Alexander Popovadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(7), 4019; https://doi.org/10.3390/ijms23074019 - 05 Apr 2022
Cited by 18 | Viewed by 2939
Abstract
We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage [...] Read more.
We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
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Review

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22 pages, 1378 KiB  
Review
Linear and Circular Long Non-Coding RNAs in Acute Lymphoblastic Leukemia: From Pathogenesis to Classification and Treatment
by Yasen Maimaitiyiming, Linyan Ye, Tao Yang, Wenjuan Yu and Hua Naranmandura
Int. J. Mol. Sci. 2022, 23(8), 4442; https://doi.org/10.3390/ijms23084442 - 18 Apr 2022
Cited by 7 | Viewed by 3033
Abstract
The coding regions account for only a small part of the human genome, and the remaining vast majority of the regions generate large amounts of non-coding RNAs. Although non-coding RNAs do not code for any protein, they are suggested to work as either [...] Read more.
The coding regions account for only a small part of the human genome, and the remaining vast majority of the regions generate large amounts of non-coding RNAs. Although non-coding RNAs do not code for any protein, they are suggested to work as either tumor suppressers or oncogenes through modulating the expression of genes and functions of proteins at transcriptional, posttranscriptional and post-translational levels. Acute Lymphoblastic Leukemia (ALL) originates from malignant transformed B/T-precursor-stage lymphoid progenitors in the bone marrow (BM). The pathogenesis of ALL is closely associated with aberrant genetic alterations that block lymphoid differentiation and drive abnormal cell proliferation as well as survival. While treatment of pediatric ALL represents a major success story in chemotherapy-based elimination of a malignancy, adult ALL remains a devastating disease with relatively poor prognosis. Thus, novel aspects in the pathogenesis and progression of ALL, especially in the adult population, need to be further explored. Accumulating evidence indicated that genetic changes alone are rarely sufficient for development of ALL. Recent advances in cytogenic and sequencing technologies revealed epigenetic alterations including that of non-coding RNAs as cooperating events in ALL etiology and progression. While the role of micro RNAs in ALL has been extensively reviewed, less attention, relatively, has been paid to other non-coding RNAs. Herein, we review the involvement of linear and circular long non-coding RNAs in the etiology, maintenance, and progression of ALL, highlighting the contribution of these non-coding RNAs in ALL classification and diagnosis, risk stratification as well as treatment. Full article
(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia 2.0)
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