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Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches

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: 20 January 2025 | Viewed by 9936

Special Issue Editor

Dr. Yosuke Minami

E-Mail Website
Guest Editor
National Cancer Center Hospital East, Kashiwa 277-8577, Chiba, Japan
Interests: leukemia; molecular target therapy; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Leukemia is an aggressive hematologic malignancy often characterized by specific genomic alterations. The standard treatment strategy for acute leukemia largely comprises intensive chemotherapy with or without hematopoietic stem cell transplantation. However, long-term survival can be achieved in only up to approximately three-quarters of patients, even in the favorable risk group. Molecular-targeted therapy has had a significant impact on clinical practice, especially for patients with specific genomic abnormalities such as FLT3- and IDH1/2-mutations. In this Special Issue, our focus is on the cutting edge of genomic oncology and precision medicine in leukemia, and the progress from molecular pathogenesis to novel therapeutic approaches.

Dr. Yosuke Minami
Guest Editor

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Keywords

  • leukemia
  • genomic oncology
  • precision medicine
  • molecular biomarker
  • molecular targeted therapy

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Published Papers (7 papers)

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Research

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14 pages, 4146 KiB  
Article
In Vitro Purging of Acute Lymphoblastic Leukemia (B-ALL) Cells with the Use of PTL, DMAPT, or PU-H71
by Ana Elenka Ortiz-Reyes, Sergio García-Sánchez, Montserrat Serrano, Juan Carlos Núñez-Enriquez, José Antonio Alvarado-Moreno, Juan José Montesinos, Guadalupe Fajardo-Orduña, Monica L. Guzman, Miguel Angel Villasis-Keever, Ismael Mancilla-Herrera, Hector Mayani and Antonieta Chavez-Gonzalez
Int. J. Mol. Sci. 2024, 25(21), 11707; https://doi.org/10.3390/ijms252111707 - 31 Oct 2024
Viewed by 392
Abstract
Acute lymphoblastic leukemia (ALL) is a hematopoietic disorder that mainly affects the child population, and it is characterized by the presence of lymphoid progenitor or precursor cells with different genetic alterations. The origin of this disease is controversial, since some authors assumed that [...] Read more.
Acute lymphoblastic leukemia (ALL) is a hematopoietic disorder that mainly affects the child population, and it is characterized by the presence of lymphoid progenitor or precursor cells with different genetic alterations. The origin of this disease is controversial, since some authors assumed that leukemic transformation occurs in a lymphoid progenitor, and there is also evidence that suggests the existence of leukemic initiating cells (LIC). PTL, DMAPT, and PU-H71 are agents that have been shown to eliminate bulk and stem cells from myeloid leukemias, but this effect has not been analyzed in lymphoblastic leukemias. In this study, we evaluated the effect of these compounds in different populations from pediatric B-ALL. For this, bone marrow samples from pediatric patients without treatment were obtained and cultured in the presence or absence of PTL, DMAPT, and PU-H71. The viability and apoptosis index were analyzed by flow cytometry in different hematopoietic subpopulations. These observations indicate that PTL and DMAPT are able to reduce B-ALL cells with a minimum effect in normal hematopoietic and non-hematopoietic cells. In contrast, PU-H71 was able to reduce the leukemic population and had a minimal effect in normal cells. These results present evidence that PTL and DMAPT are able to abrogate in vitro different populations of B-ALL and could represent a possibility of treatment, as well as prevent disease progression or relapse. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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13 pages, 1330 KiB  
Article
Translational Research on Azacitidine Post-Remission Therapy of Acute Myeloid Leukemia in Elderly Patients (QOL-ONE Trans-2)
by Esther Natalie Oliva, Maria Cuzzola, Matteo Della Porta, Anna Candoni, Prassede Salutari, Giuseppe A. Palumbo, Gianluigi Reda, Giuseppe Iannì, Matteo Zampini, Saverio D’Amico, Giovanni Tripepi, Debora Capelli, Caterina Alati, Maria Concetta Cannatà, Pasquale Niscola, Bianca Serio, Santina Barillà, Pellegrino Musto, Ernesto Vigna, Lorella Maria Antonia Melillo, Rocco Tripepi, Maria Elena Zannier, Yasuhito Nannya, Seishi Ogawa and Corrado Mammìadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(21), 11646; https://doi.org/10.3390/ijms252111646 - 30 Oct 2024
Viewed by 586
Abstract
The achievement of complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undertaking curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong disease-free survival (DFS). Our phase III study compared the efficacy and safety of [...] Read more.
The achievement of complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undertaking curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong disease-free survival (DFS). Our phase III study compared the efficacy and safety of azacitidine (AZA) to best supportive care (BSC) in elderly AML patients who achieved CR following intensive induction and consolidation therapy. This ancillary study (QOL-ONE Trans-2) evaluated biological changes in bone marrow using Next-Generation Sequencing (NGS). We analyzed baseline, randomization, and 6-month post-remission samples from 24 patients (median age of 71 and 12 males). High-throughput NGS targeted 350 myeloid malignancy-related genes, considering variants with a variant allele frequency ≥ 4%. At diagnosis, all patients had 5 to 17 (median = 10) mutations, with DNMT3A (42%), NPM1 (33%), and TET2 (33%) being most frequent. FANCA mutations in four patients were linked to a higher relapse risk (HR = 4.96, p = 0.02) for DFS at both 2 and 5 years. Further HLA-specific NGS analyses are ongoing to confirm these results and their therapeutic implications. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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17 pages, 2752 KiB  
Article
Tumor-Suppressive Cross-Linking of Anti-T. cruzi Antibodies in Acute Lymphoblastic Leukemia
by Víctor Alberto Maravelez Acosta, María del Pilar Crisóstomo Vázquez, Leticia Eligio García, Luz Ofelia Franco Sandoval, Denia Castro Pérez, Genaro Patiño López, Oscar Medina Contreras and Enedina Jiménez Cardoso
Int. J. Mol. Sci. 2024, 25(15), 8307; https://doi.org/10.3390/ijms25158307 - 30 Jul 2024
Viewed by 920
Abstract
Parasites have been associated with possible anticancer activity, including Trypanosoma cruzi, which has been linked to inhibiting the growth of solid tumors. To better understand this antitumor effect, we investigated the association of anti-T. cruzi antibodies with B cells of the [...] Read more.
Parasites have been associated with possible anticancer activity, including Trypanosoma cruzi, which has been linked to inhibiting the growth of solid tumors. To better understand this antitumor effect, we investigated the association of anti-T. cruzi antibodies with B cells of the acute lymphoblastic leukemia (ALL) SUPB15 cell line. The antibodies were generated in rabbits. IgGs were purified by affinity chromatography. Two procedures (flow cytometry (CF) and Western blot(WB)) were employed to recognize anti-T. cruzi antibodies on SUPB15 cells. We also used CF to determine whether the anti-T. cruzi antibodies could suppress SUPB15 cells. The anti-T. cruzi antibodies recognized 35.5% of the surface antigens of SUPB15. The complement-dependent cytotoxicity (CDC) results demonstrate the cross-suppression of anti-T. cruzi antibodies on up to 8.4% of SUPB15 cells. For the WB analysis, a band at 100 kDa with high intensity was sequenced using mass spectrometry, identifying the protein as nucleolin. This protein may play a role in the antitumor effect on T. cruzi. The anti-T. cruzi antibodies represent promising polyclonal antibodies that have the effect of tumor-suppressive cross-linking on cancer cells, which should be further investigated. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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23 pages, 4786 KiB  
Article
FL118 Is a Potent Therapeutic Agent against Chronic Myeloid Leukemia Resistant to BCR-ABL Inhibitors through Targeting RNA Helicase DDX5
by Kengo Takeda, Satoshi Ohta, Miu Nagao, Erika Kobayashi, Kenji Tago and Megumi Funakoshi-Tago
Int. J. Mol. Sci. 2024, 25(7), 3693; https://doi.org/10.3390/ijms25073693 - 26 Mar 2024
Cited by 2 | Viewed by 1413
Abstract
Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious [...] Read more.
Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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14 pages, 785 KiB  
Article
Comprehensive Molecular Profiling of NPM1-Mutated Acute Myeloid Leukemia Using RNAseq Approach
by Jessica Petiti, Ymera Pignochino, Aurora Schiavon, Emilia Giugliano, Enrico Berrino, Giorgia Giordano, Federico Itri, Matteo Dragani, Daniela Cilloni and Marco Lo Iacono
Int. J. Mol. Sci. 2024, 25(7), 3631; https://doi.org/10.3390/ijms25073631 - 24 Mar 2024
Cited by 1 | Viewed by 1753
Abstract
Acute myeloid leukemia (AML) is a complex hematologic malignancy with high morbidity and mortality. Nucleophosmin 1 (NPM1) mutations occur in approximately 30% of AML cases, and NPM1-mutated AML is classified as a distinct entity. NPM1-mutated AML patients without additional genetic abnormalities have a [...] Read more.
Acute myeloid leukemia (AML) is a complex hematologic malignancy with high morbidity and mortality. Nucleophosmin 1 (NPM1) mutations occur in approximately 30% of AML cases, and NPM1-mutated AML is classified as a distinct entity. NPM1-mutated AML patients without additional genetic abnormalities have a favorable prognosis. Despite this, 30–50% of them experience relapse. This study aimed to investigate the potential of total RNAseq in improving the characterization of NPM1-mutated AML patients. We explored genetic variations independently of myeloid stratification, revealing a complex molecular scenario. We showed that total RNAseq enables the uncovering of different genetic alterations and clonal subtypes, allowing for a comprehensive evaluation of the real expression of exome transcripts in leukemic clones and the identification of aberrant fusion transcripts. This characterization may enhance understanding and guide improved treatment strategies for NPM1mut AML patients, contributing to better outcomes. Our findings underscore the complexity of NPM1-mutated AML, supporting the incorporation of advanced technologies for precise risk stratification and personalized therapeutic strategies. The study provides a foundation for future investigations into the clinical implications of identified genetic variations and highlights the importance of evolving diagnostic approaches in leukemia management. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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Review

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28 pages, 2016 KiB  
Review
Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome
by Hironori Arai, Hirotaka Matsui, SungGi Chi, Yoshikazu Utsu, Shinichi Masuda, Nobuyuki Aotsuka and Yosuke Minami
Int. J. Mol. Sci. 2024, 25(1), 652; https://doi.org/10.3390/ijms25010652 - 4 Jan 2024
Cited by 3 | Viewed by 2962
Abstract
Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic [...] Read more.
Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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Other

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12 pages, 4021 KiB  
Case Report
Acute Erythroid Leukemia Post-Chemo-Radiotherapy and Autologous Stem Cell Transplantation Due to Multiple Myeloma: Tracing the Paths to Leukemic Transformation
by Gábor Méhes, Attila Mokánszki, Anikó Ujfalusi, Zsuzsa Hevessy, Zsófia Miltényi, Lajos Gergely and Judit Bedekovics
Int. J. Mol. Sci. 2024, 25(14), 8003; https://doi.org/10.3390/ijms25148003 - 22 Jul 2024
Viewed by 1170
Abstract
The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by [...] Read more.
The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by specific genetic alterations, most importantly multi-allelic mutations of the TP53 gene. While AEL might appear as a part of the therapy-related MDS/AML, spectrum information regarding the genetic complexity and progression is largely missing. We present two AEL cases arising after cytotoxic therapy and melphalan-based myeloablation/autologous peripheral stem cell transplantation due to multiple myeloma (MM). As stated, multiple pathogenic TP53 variants were present unrelated to preexisting MM, in parallel with uninvolved/wild-type hemopoiesis. Potential mechanisms of leukemic transformation are discussed, which include (1) preexisting preneoplastic hemopoietic stem cells (HSC) serving as the common origin for both MM and AEL, (2) the generation and intramedullary survival of p53-deficient post-chemotherapy HSCs, (3) reinoculation of mobilized autologous TP53 mutated HSCs, and (4) melphalan treatment-related late-onset myelodysplasia/leukemia with newly acquired TP53 mutations. Full article
(This article belongs to the Special Issue Genomic Oncology and Medicine in Leukemia: From Molecular Pathogenesis to Novel Therapeutic Approaches)
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