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Deciphering the Therapeutic Resistance of Hematologic Malignancies

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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 October 2022) | Viewed by 21935

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Special Issue Editor

Prof. Dr. Tomáš Stopka

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Guest Editor

Department of Haematology, First Faculty of Medicine, Charles University and General Hospital, 12808 Prague, Czech Republic
Interests: RNA; cancer

Special Issue Information

Dear Colleagues,

Tumor biology has decades of history in deciphering therapies to fight the hyperproliferative nature of many tumors, especially in hematology. Recent discoveries in stem cell biology have led to the development of the concept of leukemia-initiating cells. Despite many attempts to identify novel drugs with antitumor function, a large proportion of patients relapse or progress onto other therapies. The mechanisms that remain behind therapeutic resistance in leukemias and lymphomas are the subject to this Special Issue of IJMS. We are open to publications that focus on delineating genetic or epigenetic mechanisms of resistance as well as biomarker studies that associate biological parameters with adverse clinical outcome.

Prof. Dr. Tomáš Stopka
Guest Editor

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.

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Keywords

Myelodysplasia
leukemogenesis
Epigenetic regulation
Azacitidine

Published Papers (7 papers)

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Research

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16 pages, 2412 KiB

Open AccessArticle

Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression

by Uly Sumarni, Jiaqi Zhu, Tobias Sinnberg and Jürgen Eberle

Int. J. Mol. Sci. 2022, 23(20), 12471; https://doi.org/10.3390/ijms232012471 - 18 Oct 2022

Cited by 2 | Viewed by 1257

Abstract

Long-term, curative treatment of cutaneous T-cell lymphomas (CTCL) remains a major challenge. Therapy resistance is often based on apoptosis deficiency, and may depend on antiapoptotic Bcl-2 proteins, such as Bcl-2, Bcl-x_L, Bcl-w and Mcl-1. For their targeting, several antagonists have been generated, which mimic the Bcl-2 homology domain 3 (BH3 mimetics). As dysregulation and overexpression of Mcl-1 has been reported in CTCL, the use of Mcl-1 inhibitors appears as an attractive strategy. Here, we investigated the effects of the selective Mcl-1 inhibitor S63845 in a series of four CTCL cell lines, in comparison to ABT-263 and ABT-737 (inhibitors of Bcl-2, Bcl-x_L and Bcl-w). In two cell lines (HH, HuT-78), S63845 resulted in significant apoptosis induction, decrease in cell viability, loss of mitochondrial membrane potential and caspase activation, while two other cell lines (MyLa, SeAx) remained completely resistant. An inverse correlation was found, as S63845-resistant cells were highly sensitive to ABT-263/-737, and S63845-sensitive cells showed only moderate sensitivity to ABTs. Combinations of S63845 and ABT-263 partially yielded synergistic effects. As concerning Bcl-2 protein expression, weaker Mcl-1 expression was found in S63845-resistant MyLa and SeAx, while for Bcl-2 and Bcl-x_L, the lowest expression was found in the highly sensitive cell line HH. The most striking difference between S63845-resistant and -sensitive cells was identified for Bcl-w, which was exclusively expressed in S63845-resistant cells. Thus, CTCL may be efficiently targeted by BH3 mimetics, providing the right target is preselected, and Bcl-w expression may serve as a suitable marker. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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15 pages, 4839 KiB

Open AccessArticle

Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents

by Petra Bašová, Helena Paszeková, Lubomír Minařík, Martina Dluhošová, Pavel Burda and Tomáš Stopka

Int. J. Mol. Sci. 2022, 23(12), 6729; https://doi.org/10.3390/ijms23126729 - 16 Jun 2022

Cited by 4 | Viewed by 1714

Abstract

The transcription factor PU.1 (Purine-rich DNA binding, SPI1) is a key regulator of hematopoiesis, whose level is influenced by transcription through its enhancers and its post-transcriptional degradation via microRNA-155 (miR-155). The degree of transcriptional regulation of the PU.1 gene is influenced by repression via DNA methylation, as well as other epigenetic factors, such as those related to progenitor maturation status, which is modulated by the transcription factor Myeloblastosis oncogene (MYB). In this work, we show that combinatorial treatment of acute myeloid leukemia (AML) cells with DNA methylation inhibitors (5-Azacytidine), MYB inhibitors (Celastrol), and anti-miR-155 (AM155) ideally leads to overproduction of PU.1. We also show that PU.1 reactivation can be compensated by miR-155 and that only a combined approach leads to sustained PU.1 derepression, even at the protein level. The triple effect on increasing PU.1 levels in myeloblasts stimulates the myeloid transcriptional program while inhibiting cell survival and proliferation, leading to partial leukemic differentiation. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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Figure 1

12 pages, 1830 KiB

Open AccessArticle

Melittin Increases Cisplatin Sensitivity and Kills KM-H2 and L-428 Hodgkin Lymphoma Cells

by Teresa Kreinest, Ines Volkmer and Martin S. Staege

Int. J. Mol. Sci. 2021, 22(1), 343; https://doi.org/10.3390/ijms22010343 - 31 Dec 2020

Cited by 7 | Viewed by 2440

Abstract

Hodgkin lymphoma (HL) is neoplasia with high cure rates. However, not all patients can be cured with the current treatment. Chemo-resistance of tumor cells is one factor involved in treatment failure. In addition to its pore-forming activity on lipid bilayer membranes, the toxin melittin from bee venom is an inhibitor of several cancer-related signaling pathways. Moreover, melittin analogs have been shown to inhibit the activity of ATP binding cassette (ABC) transporters which are known to play important roles in the chemo-resistance of tumor cells. Therefore, we tested the toxicity of melittin for HL cell lines KM-H2 and L-428 and whether melittin can increase the chemo-sensitivity of cisplatin-resistant HL cells. We found high toxicity of melittin for KM-H2 and L-428 cells. In co-cultures with normal blood cells, melittin preferentially killed KM-H2 and L-428 cells. In addition, we observed increased cisplatin sensitivity of chemo-resistant L-428 cells after treatment with melittin. ABC transporter activity was not reduced after treatment with melittin. Our data suggest that melittin or melittin analogs might be promising agents for the future development of treatment strategies for HL patients with resistant disease. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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10 pages, 3862 KiB

Open AccessCommunication

Identification of Lenalidomide Sensitivity and Resistance Mechanisms in Non-Del(5q) Myelodysplastic Syndromes

by Leylah M. Drusbosky and Christopher R. Cogle

Int. J. Mol. Sci. 2020, 21(9), 3323; https://doi.org/10.3390/ijms21093323 - 8 May 2020

Cited by 4 | Viewed by 2111

Abstract

Whereas lenalidomide is an effective therapy for del(5q) MDS patients, a minority of non-del(5q) MDS patients achieve hematologic improvement with lenalidomide. We used computational biology modeling and digital drug simulation to examine genomic data from 56 non-del(5q) MDS patients treated with lenalidomide, and then matched treatment response with molecular pathways. The computer inferred genomic abnormalities associating with lenalidomide treatment response in non-del(5q) MDS to include trisomy 8, del(20q), or RUNX1 loss of function mutations. Genomic abnormalities associating with lenalidomide resistance in non-del(5q) MDS patients included mutations in SF3B1, TET2, WNT3A amplification, MCL1 amplification, and/or PSEN2 amplification. These results may inform protocols for determining appropriateness of lenalidomide in non-del(5q) MDS. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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Review

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28 pages, 886 KiB

Open AccessReview

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

by Krzysztof Jędraszek, Marta Malczewska, Karolina Parysek-Wójcik and Monika Lejman

Int. J. Mol. Sci. 2022, 23(6), 3067; https://doi.org/10.3390/ijms23063067 - 12 Mar 2022

Cited by 5 | Viewed by 4444

Abstract

Despite the rapid development of medicine, even nowadays, acute lymphoblastic leukemia (ALL) is still a problem for pediatric clinicians. Modern medicine has reached a limit of curability even though the recovery rate exceeds 90%. Relapse occurs in around 20% of treated patients and, regrettably, 10% of diagnosed ALL patients are still incurable. In this article, we would like to focus on the treatment resistance and disease relapse of patients with B-cell leukemia in the context of prognostic factors of ALL. We demonstrate the mechanisms of the resistance to steroid therapy and Tyrosine Kinase Inhibitors and assess the impact of genetic factors on the treatment resistance, especially TCF3::HLF translocation. We compare therapeutic protocols and decipher how cancer cells become resistant to innovative treatments—including CAR-T-cell therapies and monoclonal antibodies. The comparisons made in our article help to bring closer the main factors of resistance in hematologic malignancies in the context of ALL. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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27 pages, 1219 KiB

Open AccessReview

Molecular Aspects of Resistance to Immunotherapies—Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma

by Aleksandra Kusowska, Matylda Kubacz, Marta Krawczyk, Aleksander Slusarczyk, Magdalena Winiarska and Malgorzata Bobrowicz

Int. J. Mol. Sci. 2022, 23(3), 1501; https://doi.org/10.3390/ijms23031501 - 28 Jan 2022

Cited by 12 | Viewed by 5302

Abstract

Despite the unquestionable success achieved by rituximab-based regimens in the management of diffuse large B-cell lymphoma (DLBCL), the high incidence of relapsed/refractory disease still remains a challenge. The widespread clinical use of chemo-immunotherapy demonstrated that it invariably leads to the induction of resistance; however, the molecular mechanisms underlying this phenomenon remain unclear. Rituximab-mediated therapeutic effect primarily relies on complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity, and their outcome is often compromised following the development of resistance. Factors involved include inherent genetic characteristics and rituximab-induced changes in effectors cells, the role of ligand/receptor interactions between target and effector cells, and the tumor microenvironment. This review focuses on summarizing the emerging advances in the understanding of the molecular basis responsible for the resistance induced by various forms of immunotherapy used in DLBCL. We outline available models of resistance and delineate solutions that may improve the efficacy of standard therapeutic protocols, which might be essential for the rational design of novel therapeutic regimens. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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16 pages, 1090 KiB

Open AccessReview

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

by Carmelo Gurnari, Simona Pagliuca and Valeria Visconte

Int. J. Mol. Sci. 2020, 21(22), 8505; https://doi.org/10.3390/ijms21228505 - 12 Nov 2020

Cited by 13 | Viewed by 3728

Abstract

Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40–60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies’ (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness. Full article

(This article belongs to the Special Issue Deciphering the Therapeutic Resistance of Hematologic Malignancies)

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