Topic Editors

Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Mexico
School of Medicine, University of Colima, Colima 28040, Mexico

New Molecular Targets and Novel Strategies in Drug Development to Prevent Relapse in Acute Leukemia

Abstract submission deadline
closed (31 August 2023)
Manuscript submission deadline
closed (31 October 2023)
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7362

Topic Information

Dear Colleagues,

Acute leukemia (AL) is a heterogeneous group of hematological malignancies originating from immature progenitors of myeloid or T/B cell lymphoid lineages. Leukemogenesis results from the accumulation of genetic alterations in leukocyte progenitors that prevent their further maturation and cause unlimited proliferation. Initially, malignant cells accumulate within the bone marrow (BM), where they crowd out healthy lymphoid precursors, devastate hematopoietic niches, and impair hematopoiesis. Subsequently, some of the malignant cells leave the BM and enter the extramedullary organs, including the lymph nodes, spleen, liver, mediastinal space, and the central nervous system. Although conventional therapies, such as using high-dose multi-agent protocols (glucocorticoids, genotoxic/cytotoxic drugs) and allogenic hematopoietic stem cell transplantation, are effective in achieving remission in many patients, some groups are resistant to them. The small number of chemoresistant leukemic cells that remain after treatment are the main cause of minimal residual disease and subsequent relapse. Understanding the underlying mechanisms of chemoresistance may reveal new molecular targets and allow for the development of novel pharmacological strategies for overcoming AL relapse. Several mechanisms have been proposed as causes of chemoresistance in AL, including epigenetic alterations, metabolic reprogramming, alterations in signaling pathways, a protective microenvironment in leukemogenic niches in BM, alterations in the regulation of autophagy and apoptosis, and the overexpression of multidrug resistance pumps and proteins, among others. This Topic will focus on the current progress towards overcoming chemoresistance in AL by identifying additional molecular and cellular targets and through the application of non-conventional drugs, either alone or in combination with conventional antileukemic agents. Both review and original articles are welcome, as are pre-clinical, translational and clinical studies.

Prof. Dr. Oxana Dobrovinskaya
Dr. Ivan Delgado-Enciso
Topic Editors

Keywords

  • acute lymphoblastic leukemia
  • acute myeloblastic leukemia
  • minimal residual disease
  • leukemic stem cells
  • leukemia initiating cells
  • leukemic niche
  • metabolic reprogramming
  • chemotherapy
  • targeted therapy
  • immunotherapy
  • RNA therapeutics
  • epigenetic drugs
  • BCL-2 inhibitors
  • small molecule inhibitors
  • autophagy

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700
Diagnostics
diagnostics
3.6 3.6 2011 20.7 Days CHF 2600
Future Pharmacology
futurepharmacol
- - 2021 20.5 Days CHF 1000
Pharmaceutics
pharmaceutics
5.4 6.9 2009 14.2 Days CHF 2900

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Published Papers (3 papers)

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18 pages, 10682 KiB  
Article
MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis
by Hexiao Zhang, Fei Li, Ming Yang, Wenshan Zhang, Mei He, Hui Xu, Chaoqun Wang, Yiran Zhang, Wei Wang, Yingdai Gao, Xue Du and Yinghui Li
Pharmaceutics 2023, 15(4), 1085; https://doi.org/10.3390/pharmaceutics15041085 - 28 Mar 2023
Viewed by 1547
Abstract
Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), [...] Read more.
Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), an important pro-survival protein in the BCL-2 family, is a promising antitumor target. In this study, we chose to investigate the effects of S63845, a small-molecule inhibitor that targets MCL-1, on the normal hematopoietic system. A mouse model of hematopoietic injury was constructed, and the effects of the inhibitor on the hematopoietic system of mice were evaluated via routine blood tests and flow cytometry. The results showed that S63845 affected the hematopoiesis of various lineages in the early stage of action, causing extramedullary compensatory hematopoiesis in the myeloid and megakaryocytic lineages. The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects. Full article
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29 pages, 14110 KiB  
Article
Dexamethasone-Induced Fatty Acid Oxidation and Autophagy/Mitophagy Are Essential for T-ALL Glucocorticoid Resistance
by Miguel Olivas-Aguirre, Jesús Pérez-Chávez, Liliana Torres-López, Arturo Hernández-Cruz, Igor Pottosin and Oxana Dobrovinskaya
Cancers 2023, 15(2), 445; https://doi.org/10.3390/cancers15020445 - 10 Jan 2023
Cited by 6 | Viewed by 3415
Abstract
ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study [...] Read more.
ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines: resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagy/mitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance. Full article
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20 pages, 5888 KiB  
Article
The Translational Landscape Revealed the Sequential Treatment Containing ATRA plus PI3K/AKT Inhibitors as an Efficient Strategy for AML Therapy
by Ke Wang, Ziyao Ou, Ge Deng, Shufang Li, Jingjing Su, Yayun Xu, Renpeng Zhou, Wei Hu and Feihu Chen
Pharmaceutics 2022, 14(11), 2329; https://doi.org/10.3390/pharmaceutics14112329 - 28 Oct 2022
Cited by 2 | Viewed by 1424
Abstract
The present study aimed to better understand the possibility of utilizing all-trans retinoic acids (ATRA) in acute myeloid leukemia (AML). We found that ATRA significantly suppressed global translation and protein synthesis in AML cells. The efficacy of ATRA in treating AML required its [...] Read more.
The present study aimed to better understand the possibility of utilizing all-trans retinoic acids (ATRA) in acute myeloid leukemia (AML). We found that ATRA significantly suppressed global translation and protein synthesis in AML cells. The efficacy of ATRA in treating AML required its translational regulatory functions, as shown by the fact that the decrease in the universal eukaryotic initiation factor 4E (eIF4E) was essential to maintain the induction of cell growth arrest and differentiation by ATRA. By establishing a specific translational landscape, we suggested that transcripts with simple 5′UTR gained a translational advantage in AML cells during ATRA stress. Based on that, the genes translationally regulated by ATRA were mainly enriched in phosphatidylinositol-3-kinase/Akt (PI3K/AKT) signaling; we subsequently revealed that PI3K/AKT activation was required for ATRA to effectively induce AML cell differentiation. However, PI3K/AKT has been reported to promote the stemness of AML cells. As such, we further suggested that sequential treatment including ATRA and PI3K/AKT inhibitor induced robust apoptosis, extremely inhibited the clonality of AML cells, and suppressed the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-driven transformation of CD34+ hematopoietic stem/progenitor cells. Future clinical studies are warranted to further support the clinical application of the sequential strategy for the effective treatment of AML. Full article
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