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Metabolism and Leukemia: From Biology to Therapies
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Metabolism and Leukemia: From Biology to Therapies

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

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 25383

Special Issue Editor

Dr. Cristina Papayannidis

E-Mail
Guest Editor
Department of Hematology and Oncology "L. and A. Seràgnoli", S.Orsola Malpighi University Hospital, Bologna, Italy
Interests: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Target therapy; Monoclonal Antibodies; Mastocytosis; Tyrosine Kinase Inhibitors

Special Issue Information

Dear Colleagues,

Altered metabolism plays a key role in malignancies, and has recently been defined as an emerging hallmark of cancer. This is true also in the setting of haematological neoplasms, including Acute Myeloid and Lymphoblastic Leukemias, which utilize altered metabolism to maximize cell growth and survival. In detail, many studies in literature demonstrated that, in order to maintain cell proliferation, expansion and survival, a reprogramming of metabolism must be performed to satisfy key bioenergetics, biosynthetic, and redox functions of leukemic cells. Furthermore, several metabolites have a signaling function and promote tumor growth and progression. The importance of metabolic adaptation for the survival of AML cells and the therapeutic potential of addressing different metabolic pathways have already been reported. As a consequence, starting from this rationale, in the last few years, several drugs have been developed to target specific metabolic pathways and enzymes, metabolites, and signaling pathways. Several studies, some of which are currently ongoing, have shown an acceptable safety profile of some of these metabolism-affecting drugs, even when used in combination with standard chemotherapy, which still represents the first line therapeutic option for fit AML and ALL patients. Nevertheless, in relapsed settings and in unfit/elderly populations, innovative therapeutic options are strongly required, and targeting metabolism may represent an attractive tool.

In this Special Issue, we're going to highlight the most recent data in the field, from biological setting to therapeutic implications.

Dr. Cristina Papayannidis
Guest Editor

Manuscript Submission Information

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Keywords

  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Metabolism
  • IDH1-2
  • Glycolysis
  • Enzyme
  • pathway
  • PI3K AKT
  • mTOR
  • Asparaginase

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Published Papers (6 papers)

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Research

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19 pages, 5202 KiB  
Article
Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5′AMP-Activated Kinase Inactivation
by Valeria Tosello, Deborah Bongiovanni, Ludovica Di Martino, Cinzia Franchin, Paola Zanovello, Giorgio Arrigoni and Erich Piovan
Int. J. Mol. Sci. 2021, 22(12), 6384; https://doi.org/10.3390/ijms22126384 - 15 Jun 2021
Cited by 3 | Viewed by 2425
Abstract
Numerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to [...] Read more.
Numerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to metabolically adverse conditions, we executed quantitative phospho-proteomics in T-cell acute lymphoblastic leukemia (T-ALL) cells subjected to nutrient-depleted conditions (serum starvation). We found important modulations of peptides phosphorylated by critical signaling pathways including casein kinase, mammalian target of rapamycin, and 5′AMP-activated kinase (AMPK). Surprisingly, in T-ALL cells, AMPK signaling was the most consistently downregulated pathway under serum-depleted conditions, and this coincided with increased GLI1 expression and sensitivity to iHHs, especially the GLI1/2 inhibitor GANT-61. Increased sensitivity to GANT-61 was also found following genetic inactivation of the catalytic subunit of AMPK (AMPKα1) or pharmacological inhibition of AMPK by Compound C. Additionally, patient-derived xenografts showing high GLI1 expression lacked activated AMPK, suggesting an important role for this signaling pathway in regulating GLI1 protein levels. Further, joint targeting of HH and AMPK signaling pathways in T-ALL cells by GANT-61 and Compound C significantly increased the therapeutic response. Our results suggest that metabolic adaptation that occurs under nutrient starvation in T-ALL cells increases responsiveness to HH pathway inhibitors through an AMPK-dependent mechanism and that joint therapeutic targeting of AMPK signaling and HH signaling could represent a valid therapeutic strategy in rapidly expanding tumors where nutrient availability becomes limiting. Full article
(This article belongs to the Special Issue Metabolism and Leukemia: From Biology to Therapies)
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12 pages, 4783 KiB  
Article
Urolithin A and B Alter Cellular Metabolism and Induce Metabolites Associated with Apoptosis in Leukemic Cells
by Abdulaziz Musa Alzahrani, Mohammed Razeeth Shait Mohammed, Raed Ahmed Alghamdi, Abrar Ahmad, Mazin A. Zamzami, Hani Choudhry and Mohammad Imran Khan
Int. J. Mol. Sci. 2021, 22(11), 5465; https://doi.org/10.3390/ijms22115465 - 22 May 2021
Cited by 19 | Viewed by 4904
Abstract
Leukemia is persistently a significant cause of illness and mortality worldwide. Urolithins, metabolites of ellagic acid and ellagitannins produced by gut microbiota, showed better bioactive compounds liable for the health benefits exerted by ellagic acid and ellagitannins containing pomegranate and walnuts. Here, we [...] Read more.
Leukemia is persistently a significant cause of illness and mortality worldwide. Urolithins, metabolites of ellagic acid and ellagitannins produced by gut microbiota, showed better bioactive compounds liable for the health benefits exerted by ellagic acid and ellagitannins containing pomegranate and walnuts. Here, we assessed the potential antileukemic activities of both urolithin A and urolithin B. Results showed that both urolithin A and B significantly inhibited the proliferation of leukemic cell lines Jurkat and K562, among which urolithin A showed the more prominent antiproliferative capability. Further, urolithin treatment alters leukemic cell metabolism, as evidenced by increased metabolic rate and notable changes in glutamine metabolism, one-carbon metabolism, and lipid metabolism. Next, we evidenced that both urolithins equally promoted apoptosis in leukemic cell lines. Based on these observations, we concluded that both urolithin A and B alter leukemic cell metabolome, resulting in a halt of proliferation, followed by apoptosis. The data can be used for designing new combinational therapies to eradicate leukemic cells. Full article
(This article belongs to the Special Issue Metabolism and Leukemia: From Biology to Therapies)
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Review

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14 pages, 735 KiB  
Review
Myelodysplastic Syndromes and Metabolism
by Ekaterina Balaian, Manja Wobus, Martin Bornhäuser, Triantafyllos Chavakis and Katja Sockel
Int. J. Mol. Sci. 2021, 22(20), 11250; https://doi.org/10.3390/ijms222011250 - 19 Oct 2021
Cited by 11 | Viewed by 4828
Abstract
Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral [...] Read more.
Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions. Full article
(This article belongs to the Special Issue Metabolism and Leukemia: From Biology to Therapies)
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21 pages, 1668 KiB  
Review
Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia
by Ludovica Di Martino, Valeria Tosello, Edoardo Peroni and Erich Piovan
Int. J. Mol. Sci. 2021, 22(16), 8738; https://doi.org/10.3390/ijms22168738 - 14 Aug 2021
Cited by 15 | Viewed by 4327
Abstract
Acute leukemias, classified as acute myeloid leukemia and acute lymphoblastic leukemia, represent the most prevalent hematologic tumors in adolescent and young adults. In recent years, new challenges have emerged in order to improve the clinical effectiveness of therapies already in use and reduce [...] Read more.
Acute leukemias, classified as acute myeloid leukemia and acute lymphoblastic leukemia, represent the most prevalent hematologic tumors in adolescent and young adults. In recent years, new challenges have emerged in order to improve the clinical effectiveness of therapies already in use and reduce their side effects. In particular, in this scenario, metabolic reprogramming plays a key role in tumorigenesis and prognosis, and it contributes to the treatment outcome of acute leukemia. This review summarizes the latest findings regarding the most relevant metabolic pathways contributing to the continuous growth, redox homeostasis, and drug resistance of leukemia cells. We describe the main metabolic deregulations in acute leukemia and evidence vulnerabilities that could be exploited for targeted therapy. Full article
(This article belongs to the Special Issue Metabolism and Leukemia: From Biology to Therapies)
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15 pages, 900 KiB  
Review
MicroRNA as a Prognostic and Diagnostic Marker in T-Cell Acute Lymphoblastic Leukemia
by Katarzyna Gębarowska, Anna Mroczek, Jerzy R. Kowalczyk and Monika Lejman
Int. J. Mol. Sci. 2021, 22(10), 5317; https://doi.org/10.3390/ijms22105317 - 18 May 2021
Cited by 19 | Viewed by 3680
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is a biologically and genetically heterogeneous disease with a poor prognosis overall and several subtypes. The neoplastic transformation takes place through the accumulation of numerous genetic and epigenetic abnormalities. There are only a few prognostic factors in [...] Read more.
T cell acute lymphoblastic leukemia (T-ALL) is a biologically and genetically heterogeneous disease with a poor prognosis overall and several subtypes. The neoplastic transformation takes place through the accumulation of numerous genetic and epigenetic abnormalities. There are only a few prognostic factors in comparison to B cell precursor acute lymphoblastic leukemia, which is characterized by a lower variability and more homogeneous course. The microarray and next-generation sequencing (NGS) technologies exploring the coding and non-coding part of the genome allow us to reveal the complexity of the genomic and transcriptomic background of T-ALL. miRNAs are a class of non-coding RNAs that are involved in the regulation of cellular functions: cell proliferations, apoptosis, migrations, and many other processes. No miRNA has become a significant prognostic and diagnostic factor in T-ALL to date; therefore, this topic of investigation is extremely important, and T-ALL is the subject of intensive research among scientists. The altered expression of many genes in T-ALL might also be caused by wide miRNA dysregulation. The following review focuses on summarizing and characterizing the microRNAs of pediatric patients with T-ALL diagnosis and their potential future use as predictive factors. Full article
(This article belongs to the Special Issue Metabolism and Leukemia: From Biology to Therapies)
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16 pages, 1128 KiB  
Review
The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies
by Carmelo Gurnari, Simona Pagliuca and Valeria Visconte
Int. J. Mol. Sci. 2021, 22(6), 3135; https://doi.org/10.3390/ijms22063135 - 19 Mar 2021
Cited by 9 | Viewed by 4360
Abstract
The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a [...] Read more.
The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways. Full article
(This article belongs to the Special Issue Metabolism and Leukemia: From Biology to Therapies)
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