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Mechanisms of Disease Progression and Drug Resistance in Myeloid Malignancies
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Mechanisms of Disease Progression and Drug Resistance in Myeloid Malignancies

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

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 10674

Special Issue Editors

Dr. Anna Eiring

E-Mail Website
Guest Editor
Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
Interests: myeloid leukemia; cancer biology; cell signaling
Special Issues, Collections and Topics in MDPI journals
Dr. Jamshid Khorashad

E-Mail Website
Guest Editor
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Interests: myeloid malignancies; chronic myeloid leukemia; acute myeloid leukemia; chronic myelomonocytic leukemia

Special Issue Information

Dear Colleagues,

Recent advances in laboratory and clinical science have improved outcomes for patients with myeloid malignancies. Despite this success, clinical challenges remain, and there is a great need to identify novel molecular targets and therapies to prevent disease progression and drug resistance. This special issue of International Journal of Molecular Sciences seeks recent original research in the field of myeloid malignancies, including the development of new insights and/or reviews in the field. We are particularly interested in leukemia stem cell research, novel therapeutics, new biomarkers, and epidemiological studies. Please contact the guest editors if you would like to discuss an idea for a paper prior to submission.

Dr. Anna Eiring
Dr. Jamshid Khorashad
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

  • myeloid malignancies
  • chronic myeloid leukemia
  • chronic myelomonocytic leukemia
  • acute myeloid leukemia
  • myelodysplastic syndrome
  • myeloproferative disease
  • leukemic stem cells
  • drug resistance

Published Papers (3 papers)

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Research

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17 pages, 2832 KiB  
Article
19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML)
by Joshua J. Lara, Alfonso E. Bencomo-Alvarez, Mayra A. Gonzalez, Idaly M. Olivas, James E. Young, Jose L. Lopez, Vanessa V. Velazquez, Steven Glovier, Mehrshad Keivan, Andres J. Rubio, Sara K. Dang, Jonathan P. Solecki, Jesse C. Allen, Desiree N. Tapia, Boranai Tychhon, Gonzalo E. Astudillo, Connor Jordan, Darshan S. Chandrashekar and Anna M. Eiring
Int. J. Mol. Sci. 2022, 23(23), 14586; https://doi.org/10.3390/ijms232314586 - 23 Nov 2022
Cited by 4 | Viewed by 2302
Abstract
26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3) were recently identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia (CML) and multiple solid tumors. In the present study, we analyzed the expression of 19S proteasome subunits in acute myeloid [...] Read more.
26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3) were recently identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia (CML) and multiple solid tumors. In the present study, we analyzed the expression of 19S proteasome subunits in acute myeloid leukemia (AML) patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene and assessed their impact on overall survival (OS). High levels of PSMD3 but not PSMD1 expression correlated with a worse OS in FLT3-mutated AML. Consistent with an oncogenic role for PSMD3 in AML, shRNA-mediated PSMD3 knockdown impaired colony formation of FLT3+ AML cell lines, which correlated with increased OS in xenograft models. While PSMD3 regulated nuclear factor-kappa B (NF-κB) transcriptional activity in CML, we did not observe similar effects in FLT3+ AML cells. Rather, proteomics analyses suggested a role for PSMD3 in neutrophil degranulation and energy metabolism. Finally, we identified additional PSMD subunits that are upregulated in AML patients with mutated versus wild-type FLT3, which correlated with worse outcomes. These findings suggest that different components of the 19S regulatory complex of the 26S proteasome can have indications for OS and may serve as prognostic biomarkers in AML and other types of cancers. Full article
(This article belongs to the Special Issue Mechanisms of Disease Progression and Drug Resistance in Myeloid Malignancies)
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22 pages, 4708 KiB  
Article
The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins
by Margarita Kobyakova, Yana Lomovskaya, Anatoly Senotov, Alexey Lomovsky, Vladislav Minaychev, Irina Fadeeva, Daria Shtatnova, Kirill Krasnov, Alena Zvyagina, Irina Odinokova, Vladimir Akatov and Roman Fadeev
Int. J. Mol. Sci. 2022, 23(14), 7881; https://doi.org/10.3390/ijms23147881 - 17 Jul 2022
Cited by 10 | Viewed by 3585
Abstract
It is known that cell culture density can modulate the drug resistance of acute myeloid leukemia (AML) cells. In this work, we studied the drug sensitivity of AML cells in high-density cell cultures (cell lines THP-1, HL-60, MV4-11, and U937). It was shown [...] Read more.
It is known that cell culture density can modulate the drug resistance of acute myeloid leukemia (AML) cells. In this work, we studied the drug sensitivity of AML cells in high-density cell cultures (cell lines THP-1, HL-60, MV4-11, and U937). It was shown that the AML cells in high-density cell cultures in vitro were significantly more resistant to DNA-damaging drugs and recombinant ligand izTRAIL than those in low-density cell cultures. To elucidate the mechanism of the increased drug resistance of AML cells in high-density cell cultures, we studied the activation of Bcl-2, Hif-1alpha, and NF-kB proteins, as well as cytokine secretion, the inflammatory immunophenotype, and the transcriptome for THP-1 cells in the low-density and high-density cultures. The results indicated that the increase in the drug resistance of proliferating THP-1 cells in high-density cell cultures was associated with the accumulation of inflammatory cytokines in extracellular medium, and the formation of NF-kB-dependent inflammatory-like cell activation with the anti-apoptotic proteins Bcl-2 and Bcl-xl. The increased drug resistance of THP-1 cells in high-density cultures can be reduced by ABT-737, an inhibitor of Bcl-2 family proteins, and by inhibitors of NF-kB. The results suggest a mechanism for increasing the drug resistance of AML cells in the bone marrow and are of interest for developing a strategy to suppress this resistance. Full article
(This article belongs to the Special Issue Mechanisms of Disease Progression and Drug Resistance in Myeloid Malignancies)
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Review

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22 pages, 1694 KiB  
Review
Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors
by Daisuke Ikeda, SungGi Chi, Satoshi Uchiyama, Hirotaka Nakamura, Yong-Mei Guo, Nobuhiko Yamauchi, Junichiro Yuda and Yosuke Minami
Int. J. Mol. Sci. 2022, 23(11), 5950; https://doi.org/10.3390/ijms23115950 - 25 May 2022
Cited by 12 | Viewed by 4085
Abstract
The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of [...] Read more.
The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms. Different adverse genetic factors often rely on common pathways. KMT2A rearrangement, DEK-NUP214 fusion, and NPM1 mutation are associated with the upregulation of HOX genes. The dominant tyrosine kinase activity of the mutant FLT3 or BCR-ABL1 fusion proteins is transduced by the AKT-mTOR, MAPK-ERK, and STAT5 pathways. Concurrent mutations of ASXL1 and RUNX1 are associated with activated AKT. Both TP53 mutation and mis-expressed MECOM are related to impaired apoptosis. Clinical data suggest that adverse genetic factors can be found in at least one in eight AML patients and appear to accumulate in relapsed/refractory cases. TP53 mutation is associated with particularly poor prognosis. Molecular-targeted therapies focusing on specific genomic abnormalities, such as FLT3, KMT2A, and TP53, have been developed and have demonstrated promising results. Full article
(This article belongs to the Special Issue Mechanisms of Disease Progression and Drug Resistance in Myeloid Malignancies)
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