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

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

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Cancers cancers	4.5	8.0	2009	16.3 Days	CHF 2900
Cells cells	5.1	9.9	2012	17.5 Days	CHF 2700
Diagnostics diagnostics	3.0	4.7	2011	20.5 Days	CHF 2600
Future Pharmacology futurepharmacol	-	-	2021	25 Days	CHF 1000
Pharmaceutics pharmaceutics	4.9	7.9	2009	14.9 Days	CHF 2900

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Published Papers (3 papers)

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All Cancers Cells Diagnostics Future Pharmacology Pharmaceutics

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18 pages, 10682 KiB  

Open AccessArticle

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

Cited by 1 | Viewed by 1920

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

(This article belongs to the Topic New Molecular Targets and Novel Strategies in Drug Development to Prevent Relapse in Acute Leukemia)

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29 pages, 14110 KiB  

Open AccessArticle

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 10 | Viewed by 4080

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

(This article belongs to the Topic New Molecular Targets and Novel Strategies in Drug Development to Prevent Relapse in Acute Leukemia)

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20 pages, 5888 KiB  

Open AccessArticle

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 3 | Viewed by 1798

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

(This article belongs to the Topic New Molecular Targets and Novel Strategies in Drug Development to Prevent Relapse in Acute Leukemia)

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