bims-almceb 2022-03-06 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–03–06
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells.
SEPHguarding acute myeloid leukemia.
Co-targeting leukemia-initiating cells and leukemia bulk leads to disease eradication.
Are we still on the right Path(way)?: the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy.
Taking the STING out of acute myeloid leukemia through macrophage-mediated phagocytosis.
CD36: an emerging therapeutic target for cancer and its molecular mechanisms.
Different mechanisms of drug resistance to hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukemia.
Exploiting the tumor immune microenvironment and immunometabolism using mitochondria-targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research.
Editorial: Cancer Cell Metabolism and Immunomodulation in the Context of Tumor Metastasis.
NAMPT: a critical driver and therapeutic target for cancer.
The proteogenomic subtypes of acute myeloid leukemia.
Shielded geomagnetic field accelerates glucose consumption in human neuroblastoma cells by promoting anaerobic glycolysis.

Front Oncol. 2022 ;12 807266

Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells.

Yashar Mesbahi, Toby N Trahair, Richard B Lock, Patrick Connerty.

  Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.

Keywords:  acute myeloid leukaemia; cancer metabolism; leukaemic stem cells; metabolic plasticity; metabolic targeting

DOI:  https://doi.org/10.3389/fonc.2022.807266
Cell Stem Cell. 2022 Mar 03. pii: S1934-5909(22)00058-3. [Epub ahead of print]29(3): 350-352

SEPHguarding acute myeloid leukemia.

Malini Gupta, Britta Will.

Adaptive aberrant gene regulation is a hallmark of malignant growth and therapy resistance in acute myeloid leukemia (AML). In this issue of Cell Stem Cell, Eagle et al. identified oncogenic enhancer-driven overexpression of selenophosphate synthetase 2 (SEPHS2) as an opportunity for targeted mitigation of malignant cell growth in AML.

DOI: https://doi.org/10.1016/j.stem.2022.02.007
Leukemia. 2022 Mar 04.

Co-targeting leukemia-initiating cells and leukemia bulk leads to disease eradication.

Simona Moretti, Amal Kamal Abdel-Aziz, Elena Ceccacci, Isabella Pallavicini, Fabio Santoro, Hugues de Thé, Saverio Minucci.

According to a hierarchical model, targeting leukemia-initiating cells (LICs) was speculated to achieve complete remission (CR) or cure. Nonetheless, increasing evidence emphasized the plasticity of differentiated blasts undergoing interconversion into LICs. We exploited murine models of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia driven by the promyelocytic leukemia/retinoic acid receptor (PML-RARα) oncofusion protein, which recruits histone deacetylase (HDAC)-containing complexes. We studied APLs with different LIC frequencies and investigated the effect of two HDAC inhibitors: valproic acid (VPA), with relative selectivity towards class I HDAC enzymes and vorinostat/suberoylanilide hydroxamic acid (SAHA) (pan-HDAC inhibitor) in combination with all-trans retinoic acid (ATRA), on the bulk APL cells and APL LICs. Indeed, we found that while VPA differentiates the bulk APL cells, SAHA selectively targets LICs. ATRA + VPA + SAHA combination efficiently induced CR in an APL model with lower LIC frequency. Substituting ATRA with synthetic retinoids as etretinate which promotes APL differentiation without downregulating PML/RARα compromised the therapeutic benefit of ATRA + VPA + SAHA regimen. Altogether, our study emphasizes the therapeutic power of co-targeting the plasticity and heterogeneity of cancer -herein demonstrated by tackling LICs and bulk leukemic blasts - to achieve and maintain CR.

DOI: https://doi.org/10.1038/s41375-022-01530-3
Expert Opin Drug Metab Toxicol. 2022 Mar 03.

Are we still on the right Path(way)?: the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy.

Caroline J W Meskers, Marika Franczak, Ryszard T Smolenski, Elisa Giovannetti, Godefridus J Peters.

   INTRODUCTION: The pentose phosphate pathway (PPP) branches from glycolysis and is crucial for cell growth, since it provides necessary compounds for anabolic reactions, nucleotide synthesis and detoxification of reactive-oxygen-species (ROS). Overexpression of PPP enzymes has been reported in multiple cancer types and linked to therapy resistance, making their inhibition interesting targets for anti-cancer therapies.
AREAS COVERED: This review summarizes the extent of PPP upregulation across different cancer types, and the non-metabolic functions that PPP-enzymes might contribute to cancer initiation and maintenance. The effects of PPP-inhibition and their combinations with chemotherapeutics are summarized. We searched the databases provided by the University of Amsterdam to characterize the altered expression of the PPP across different cancer types, and to identify the effects of PPP-inhibition.
EXPERT OPINION: It can be concluded that there are synergistic and additive effects of PPP-inhibition and various classes of chemotherapeutics. These effects may be attributed to the increased susceptibility to ROS. However the toxicity, low efficacy and off-target effects of PPP-inhibitors make application in clinical practice challenging. Novel inhibitors are currently being developed, which could make PPP-inhibition a potential therapeutic strategy in the future, especially in combination with conventional chemotherapeutics and the inhibition of other metabolic pathways.

Keywords:  NAD/NADH; cancer; chemotherapy; glycolysis; pentose phosphate pathway

DOI:  https://doi.org/10.1080/17425255.2022.2049234
J Clin Invest. 2022 Mar 01. pii: e157434. [Epub ahead of print]132(5):

Taking the STING out of acute myeloid leukemia through macrophage-mediated phagocytosis.

William Brian Dalton, Gabriel Ghiaur, Linda Ms Resar.

Macrophages within the bone marrow (BM) microenvironment take on unexpected roles in acute myeloid leukemia (AML) as reported by Moore and colleagues in this issue of the JCI. In contrast to solid tumors, where tumor-associated macrophages frequently assume an immunosuppressive phenotype that promotes tumor progression, this study revealed that BM macrophages repressed leukemia expansion in AML through a pathway called LC3-associated phagocytosis (LAP). After phagocytosis of dead and dying leukemic cells, including the mitochondria within the leukemic blasts, mitochondrial DNA activated stimulator of IFN genes (STING), leading to inflammatory signals that enhanced phagocytosis and restrained leukemic cell expansion. These findings unveil the modulation of macrophage-mediated phagocytosis via LAP as a potential therapeutic strategy directed at the BM microenvironment in AML.

DOI: https://doi.org/10.1172/JCI157434
J Cancer Res Clin Oncol. 2022 Feb 27.

CD36: an emerging therapeutic target for cancer and its molecular mechanisms.

Chengwei Ruan, Yankai Meng, Hu Song.

  Tumor cells need to rewire their metabolic pathways to regulate the nutrient uptake and metabolism to sustain the energy production. Lipids are important components of energy sources for tumor metabolism. Tumor cells rely on various transporters to mediate the trafficking of lipids for oxidation or activate oncogenic signaling pathways. CD36, a membrane glycoprotein presenting on the surface of cells, binds fatty acids to facilitate their transport for lipid utilization. Upregulated CD36 expression has been observed in multiple cancer types including acute myeloid leukemia, breast cancer, colorectal cancer, gastric cancer, etc. Moreover, CD36 is correlated with poor clinical outcomes and adverse clinicopathological features in various cancer types. In vitro and vivo studies have confirmed that CD36 participates in the regulation of tumor growth, metastasis, drug resistance through diverse molecular mechanisms. Thus, we firstly discussed the role of CD36 in the regulation of metabolic phenotypes, especially in glucose and fatty acid metabolism. Furthermore, we specifically focused on the molecular mechanisms of CD36 in the occurrence and development of multiple tumor types. Collectively, we explored the connection between CD36 and tumors, providing new insights for developing potential therapeutic strategies and tumor stratification targeting CD36.

Keywords:  CD36; Fatty acid; Metabolism

DOI:  https://doi.org/10.1007/s00432-022-03957-8
Drug Resist Updat. 2022 Jan 21. pii: S1368-7646(22)00008-5. [Epub ahead of print]61 100805

Different mechanisms of drug resistance to hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukemia.

Kristína Šimoničová, Ľuboš Janotka, Helena Kavcová, Zdena Sulová, Albert Breier, Lucia Messingerova.

  Resistance to the hypomethylating agents (HMAs) 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) represents a major obstacle in the treatment of elderly patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) which are not suitable for hematopoietic stem cells transplantation. Approximately 50 % of patients do not respond to HMA treatment because of intrinsic (primary) resistance, while others could acquire drug resistance during the repeated cycles of the treatment. To prevent, delay or surmount resistance development, the molecular mechanisms underlying drug resistance must be first identified. This is crucial as no further standard therapeutic opportunities are available for these patients who failed hypomethylating agents-based treatment. The current review provides an updated information about the different mechanisms that may contribute to the development of resistance to HMAs. Despite the similar structure and mechanism of action of HMA, several studies did not report the expected development of cross-resistance. It is clear that in addition to the common modalities of chemoresistance, there must be some specific mechanisms of drug resistance. Changes in transport and metabolism of HMAs are among the most studied mechanisms of resistance. Drug uptake provided by two solute carrier (SLC) families: SLC28 and SLC29 (also known as the concentrative and equilibrative nucleoside transporter families, respectively), could represent one of the mechanisms of cross-resistance. Changes in the metabolism of these drugs are the most likely mechanism responsible for the unique mode of resistance to AZA and DAC. Deoxycytidine kinase and uridine-cytidine kinase due to their necessity for drug activation, each could represent one of the response markers to treatment with DAC and AZA, respectively. Other mechanisms involved in the development of resistance common for both drugs involved: i. increased DNA repair (caused for example by constitutive activation of the ATM/BRCA1 pathway and inhibition of p53-dependent apoptosis); ii. changes in the regulation of apoptosis/disrupted apoptotic pathways (specifically increased levels of the anti-apoptotic protein BCL2) and iii. increased resilience of leukemic stem cells to multiple drugs including HMAs. Despite intense research on the resistance of MDS and AML patients to HMAs, the mechanisms that may reduce the response of these cells to HMAs are not known in detail. We herein highlight the most important directions that future research should take.

Keywords:  5-aza-2'-deoxycytidine; 5-azacytidine; Acute myeloid leukemia; Hypomethylating agents; Myelodysplastic syndromes; Resistance

DOI:  https://doi.org/10.1016/j.drup.2022.100805
FASEB J. 2022 04;36(4): e22226

Exploiting the tumor immune microenvironment and immunometabolism using mitochondria-targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research.

Balaraman Kalyanaraman.

  Black and Hispanic cancer patients have a higher incidence of cancer mortality. Many factors (e.g., socioeconomic differences, insufficient access to healthcare) contribute to racial disparity. Emerging research implicates biological disparity in cancer outcomes. Studies show distinct differences in the tumor immune microenvironment (TIME) in Black cancer patients. Studies also have linked altered mitochondrial metabolism to changes in immune cell activation in TIME. Recent publications revealed a novel immunomodulatory role for triphenylphosphonium-based mitochondrial-targeted drugs (MTDs). These are synthetically modified, naturally occurring molecules (e.g., honokiol, magnolol, metformin) or FDA-approved small molecule drugs (e.g., atovaquone, hydroxyurea). Modifications involve conjugating the parent molecule via an alkyl linker chain to a triphenylphosphonium moiety. These modified molecules (e.g., Mito-honokiol, Mito-magnolol, Mito-metformin, Mito-atovaquone, Mito-hydroxyurea) accumulate in tumor cell mitochondria more effectively than in normal cells and inhibit mitochondrial respiration, induce reactive oxygen species, activate AMPK and redox transcription factors, and inhibit cancer cell proliferation. Besides these intrinsic effects of MTDs in redox signaling and proliferation in tumors, MTDs induced extrinsic effects in the TIME of mouse xenografts. MTD treatment inhibited tumor-suppressive immune cells, myeloid-derived suppressor cells, and regulatory T cells, and activated T cells and antitumor immune effects. One key biological disparity in Black cancer patients was related to altered mitochondrial oxidative metabolism; MTDs targeting vulnerabilities in tumor cells and the TIME may help us understand this biological disparity. Clinical trials should include an appropriate number of Black and Hispanic cancer patients and should validate the intratumoral, antihypoxic effects of MTDs with imaging.

Keywords:  OXPHOS inhibitors; mitochondrial drugs; racial disparity; tumor microenvironment

DOI:  https://doi.org/10.1096/fj.202101862R
Front Oncol. 2021 ;11 803213

Editorial: Cancer Cell Metabolism and Immunomodulation in the Context of Tumor Metastasis.

Qiongzhu Dong, Peter J Nelson, Yue Zhao.



Keywords:  cancer metabolism; immune evasion; immunomodulation; microenvironment; tumor metastasis

DOI:  https://doi.org/10.3389/fonc.2021.803213
Int J Biochem Cell Biol. 2022 Feb 24. pii: S1357-2725(22)00034-6. [Epub ahead of print] 106189

NAMPT: a critical driver and therapeutic target for cancer.

Massimiliano Gasparrini, Valentina Audrito.

  Nicotinamide phosphoribosyltransferase (NAMPT) possesses a vital role in mammalian cells due to its activity as a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. NAD is an essential redox cofactor, but it also functions as a substrate for NAD-consuming enzymes, regulating multiple cellular processes such as DNA repair and gene expression, fundamental to sustain tumor growth and survival and energetic needs. A common strategy that several tumor types adopt to sustain NAD synthesis is to over-express NAMPT. However, beside its intracellular functions, this enzyme has a second life outside of cells exerting cytokine-like functions and mediating pro-inflammatory conditions activating signaling pathways. While the effects of NAMPT/NAD axis on energetic metabolism in tumors has been well-established, increasing evidence demonstrated the impact of NAMPT over-expression (intra-/extra-cellular) on several tumor cellular processes, including DNA repair, gene expression, signaling pathways, proliferation, invasion, stemness, phenotype plasticity, metastatization, angiogenesis, immune regulation, and drug resistance. For all these reasons, NAMPT targeting has emerged as promising anti-cancer strategy to deplete NAD and impair cellular metabolism, but also to counteract the other NAMPT-related functions. In this review, we summarize the key role of NAMPT in multiple biological processes implicated in cancer biology and the impact of NAMPT inhibition as therapeutic strategy for cancer treatment.

Keywords:  NAD; NAMPT; cancer biology; cancer therapy; immune cell regulation; metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.biocel.2022.106189
Cancer Cell. 2022 Feb 28. pii: S1535-6108(22)00058-7. [Epub ahead of print]

The proteogenomic subtypes of acute myeloid leukemia.

Ashok Kumar Jayavelu, Sebastian Wolf, Florian Buettner, Gabriela Alexe, Björn Häupl, Federico Comoglio, Constanze Schneider, Carmen Doebele, Dominik C Fuhrmann, Sebastian Wagner, Elisa Donato, Carolin Andresen, Anne C Wilke, Alena Zindel, Dominique Jahn, Bianca Splettstoesser, Uwe Plessmann, Silvia Münch, Khali Abou-El-Ardat, Philipp Makowka, Fabian Acker, Julius C Enssle, Anjali Cremer, Frank Schnütgen, Nina Kurrle, Björn Chapuy, Jens Löber, Sylvia Hartmann, Peter J Wild, Ilka Wittig, Daniel Hübschmann, Lars Kaderali, Jürgen Cox, Bernhard Brüne, Christoph Röllig, Christian Thiede, Björn Steffen, Martin Bornhäuser, Andreas Trumpp, Henning Urlaub, Kimberly Stegmaier, Hubert Serve, Matthias Mann, Thomas Oellerich.

  Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these proteomic subtypes correlate with patient outcome, but none is exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which is captured only in the proteome, is characterized by high expression of mitochondrial proteins and confers poor outcome, with reduced remission rate and shorter overall survival on treatment with intensive induction chemotherapy. Functional analyses reveal that Mito-AML is metabolically wired toward stronger complex I-dependent respiration and is more responsive to treatment with the BCL2 inhibitor venetoclax.

Keywords:  BCL-2 inhibitor; acute myeloid leukemia; chemotherapy; mitochondrial oxidative phosphorylation; multi-omics data integration; proteogenomics; proteomics; venetoclax

DOI:  https://doi.org/10.1016/j.ccell.2022.02.006
Biochem Biophys Res Commun. 2022 Jan 31. pii: S0006-291X(22)00152-8. [Epub ahead of print]601 101-108

Shielded geomagnetic field accelerates glucose consumption in human neuroblastoma cells by promoting anaerobic glycolysis.

Guo-Mi Wang, Jing-Peng Fu, Wei-Chuan Mo, Hai-Tao Zhang, Ying Liu, Rong-Qiao He.

  A shielded geomagnetic field, also called the hypomagnetic field (HMF), interferes with the metabolic processes of various cells and animals exhibiting diverse effects in different models, however, its underlying mechanism remains largely unknown. In this study, we assessed the effect on the energy metabolism of SH-SY5Y cells in HMF and found that HMF-induced cell proliferation depends on glucose supply. HMF promoted SH-SY5Y cell proliferation by increasing glucose consumption rate via up-regulating anaerobic glycolysis in the cells. Increased activity of LDH, a key member of glycolysis, was possibly a direct response to HMF-induced cell proliferation. Thus, we unveiled a novel subcellular mechanism underlying the HMF-induced cellular response: the up-regulation of anaerobic glycolysis and repression of oxidative stress shifted cellular metabolism more towards the Warburg effect commonly observed in cancer metabolism. We suggest that cellular metabolic profiles of various cell types may determine HMF-induced cellular effects, and a magnetic field can be applied as a non-invasive regulator of cell metabolism.

Keywords:  Cell metabolism; Cell proliferation; Glycolysis; Hypomagnetic field

DOI:  https://doi.org/10.1016/j.bbrc.2022.01.114