bims-almceb 2022-07-31 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–07–31
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies.
Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets.
Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.
NF-κB: A Druggable Target in Acute Myeloid Leukemia.
Akt protein boosts cancer metabolism through a two-pronged attack.
Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Proteomic Profiling Identifies Specific Leukemic Stem Cell-Associated Protein Expression Patterns in Pediatric AML Patients.
Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation.
Immune Checkpoint Inhibitors in Cancer Therapy-How to Overcome Drug Resistance?
Bone Marrow Overexpression of SNAI1 is an early indicator of intrinsic drug resistance in patients with De Novo acute myeloid leukemia.
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.

Cancers (Basel). 2022 Jul 15. pii: 3456. [Epub ahead of print]14(14):

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies.

Mila S Griffioen, David C de Leeuw, Jeroen J W M Janssen, Linda Smit.

  Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34-90% and 21-33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.

Keywords:  AML; biomarkers; resistance; sensitivity; therapeutic combinations; venetoclax (BCL-2 inhibitor)

DOI:  https://doi.org/10.3390/cancers14143456
Cell Biol Int. 2022 Jul 28.

Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets.

Sayan Chakraborty, Poulomi Khamaru, Arindam Bhattacharyya.

  Metabolism is a dynamic process and keeps changing from time to time according to the demand of a particular cell to meet its bio-energetic requirement. Different immune cells rely on distinct metabolic programs which allow the cell to balance its requirements for energy, molecular biosynthesis, and effector activity. In the aspect of infection and cancer immunology, effector T and B cells get exhausted and help tumor cells to evade immunosurveillance. On the other hand, T cells become hyperresponsive in the scenario of autoimmune diseases. In this article, we have explored the uniqueness and distinct metabolic features of key CD4+ T and B helper cell subsets, CD4+ T, B regulatory cell subsets and CD8+ T cells regarding health and disease. Th1 cells rely on glycolysis and glutaminolysis; inhibition of these metabolic pathways promotes Th1 cells in Treg population. However, Th2 cells are also dependent on glycolysis but an abundance of lactate within TME shifts their metabolic dependency to fatty acid metabolism. Th17 cells depend on HIF-1α mediated glycolysis, ablation of HIF-1α reduces Th17 cells but enhance Treg population. In contrast to effector T cells which are largely dependent on glycolysis for their differentiation and function, Treg cells mainly rely on FAO for their function. Therefore, it is of utmost importance to understand the metabolic fates of immune cells and how it facilitates their differentiation and function for different disease models. Targeting metabolic pathways to restore the functionality of immune cells in diseased conditions can lead to potent therapeutic measures.

Keywords:  autoimmune disorders; cancer; germinal center; immune cell regulation; infectious diseases; metabolic reprogramming

DOI:  https://doi.org/10.1002/cbin.11867
Cell Commun Signal. 2022 Jul 27. 20(1): 114

Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.

Guofeng Ma, Zhilei Zhang, Peng Li, Zhao Zhang, Manqin Zeng, Zhijuan Liang, Dan Li, Liping Wang, Yuanbin Chen, Ye Liang, Haitao Niu.

  Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract.

Keywords:  Glutamine metabolism; Glutamine metabolism inhibitors; Immune response; Immunity; Reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-022-00909-0
Cancers (Basel). 2022 Jul 21. pii: 3557. [Epub ahead of print]14(14):

NF-κB: A Druggable Target in Acute Myeloid Leukemia.

Barbara Di Francesco, Daniela Verzella, Daria Capece, Davide Vecchiotti, Mauro Di Vito Nolfi, Irene Flati, Jessica Cornice, Monica Di Padova, Adriano Angelucci, Edoardo Alesse, Francesca Zazzeroni.

  Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic options are still urgently needed. Constitutive NF-κB activation has been reported in around 40% of AML patients, where it sustains AML cell survival and chemoresistance. Given the central role of NF-κB in AML, targeting the NF-κB pathway represents an attractive strategy to treat AML. This review focuses on current knowledge of NF-κB's roles in AML pathogenesis and summarizes the main therapeutic approaches used to treat NF-κB-driven AML.

Keywords:  NF-κB; NF-κB inhibitors; acute myeloid leukemia; cancer therapy; targeted therapy

DOI:  https://doi.org/10.3390/cancers14143557
Nature. 2022 Jul 27.

Akt protein boosts cancer metabolism through a two-pronged attack.

Philipp Poeller, Almut Schulze.



Keywords:  Biochemistry; Cancer; Metabolism

DOI:  https://doi.org/10.1038/d41586-022-01603-4
Cells. 2022 Jul 20. pii: 2249. [Epub ahead of print]11(14):

Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Yasmin Abaza, Amer M Zeidan.

  Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors, with limited progress made in the area of myeloid malignancies. The low mutational burden of acute myeloid leukemia (AML) is one potential reason behind the lack of activity of T-cell harnessing ICIs, particularly CTLA-4 and PD-1 inhibitors. Innate immune checkpoints play a critical role in the immune escape of AML and myelodysplastic syndromes (MDS). The CD47 targeting agent, magrolimab, has shown promising activity when combined with azacitidine in early phase trials conducted in AML and higher-risk MDS, especially among patients harboring a TP53 mutation. Similarly, sabatolimab (an anti-TIM-3 monoclonal antibody) plus hypomethylating agents have shown durable responses in higher-risk MDS and AML in early clinical trials. Randomized trials are currently ongoing to confirm the efficacy of these agents. In this review, we will present the current progress and future directions of immune checkpoint inhibition in AML and MDS.

Keywords:  CD47; TIM-3; acute myeloid leukemia; immune checkpoint inhibitors; myelodysplastic syndromes

DOI:  https://doi.org/10.3390/cells11142249
Cancers (Basel). 2022 Jul 22. pii: 3567. [Epub ahead of print]14(15):

Proteomic Profiling Identifies Specific Leukemic Stem Cell-Associated Protein Expression Patterns in Pediatric AML Patients.

Marianne Agerlund Petersen, Carina Agerbo Rosenberg, Marie Bill, Marie Beck Enemark, Ole Rahbek, Anne Stidsholt Roug, Henrik Hasle, Bent Honoré, Maja Ludvigsen.

  Novel therapeutic tools are warranted to improve outcomes for children with acute myeloid leukemia (AML). Differences in the proteome of leukemic blasts and stem cells (AML-SCs) in AML compared with normal hematopoietic stem cells (HSCs) may facilitate the identification of potential targets for future treatment strategies. In this explorative study, we used mass spectrometry to compare the proteome of AML-SCs and CLEC12A+ blasts from five pediatric AML patients with HSCs and hematopoietic progenitor cells from hematologically healthy, age-matched controls. A total of 456 shared proteins were identified in both leukemic and control samples. Varying protein expression profiles were observed in AML-SCs and leukemic blasts, none having any overall resemblance to healthy counterpart cell populations. Thirty-four proteins were differentially expressed between AML-SCs and HSCs, including the upregulation of HSPE1, SRSF1, and NUP210, and the enrichment of proteins suggestive of protein synthesis perturbations through the downregulation of EIF2 signaling was found. Among others, NUP210 and calreticulin were upregulated in CLEC12A+ blasts compared with HSCs. In conclusion, the observed differences in protein expression between pediatric patients with AML and pediatric controls, in particular when comparing stem cell subsets, encourages the extended exploration of leukemia and AML-SC-specific biomarkers of potential relevance in the development of future therapeutic options in pediatric AML.

Keywords:  hematopoietic stem cells; mass spectrometry; pediatric acute myeloid leukemia; proteomics

DOI:  https://doi.org/10.3390/cancers14153567
Molecules. 2022 Jul 07. pii: 4350. [Epub ahead of print]27(14):

Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation.

Maira Smaniotto Cucielo, Roberta Carvalho Cesário, Henrique Spaulonci Silveira, Letícia Barbosa Gaiotte, Sérgio Alexandre Alcantara Dos Santos, Debora Aparecida Pires de Campos Zuccari, Fábio Rodrigues Ferreira Seiva, Russel J Reiter, Luiz Gustavo de Almeida Chuffa.

  Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.

Keywords:  SKOV-3 cells; Warburg effect; glucose; melatonin; mitochondrial metabolism; ovarian cancer

DOI:  https://doi.org/10.3390/molecules27144350
Cancers (Basel). 2022 Jul 22. pii: 3575. [Epub ahead of print]14(15):

Immune Checkpoint Inhibitors in Cancer Therapy-How to Overcome Drug Resistance?

Yefang Lao, Daoming Shen, Weili Zhang, Rui He, Min Jiang.

  Immune checkpoint inhibitors (ICIs), antagonists used to remove tumor suppression of immune cells, have been widely used in clinical settings. Their high antitumor effect makes them crucial for treating cancer after surgery, radiotherapy, chemotherapy, and targeted therapy. However, with the advent of ICIs and their use by a large number of patients, more clinical data have gradually shown that some cancer patients still have resistance to ICI treatment, which makes some patients unable to benefit from their antitumor effect. Therefore, it is vital to understand their antitumor and drug resistance mechanisms. In this review, we focused on the antitumor action sites and mechanisms of different types of ICIs. We then listed the main possible mechanisms of ICI resistance based on recent studies. Finally, we proposed current and future solutions for the resistance of ICIs, providing theoretical support for improving their clinical antitumor effect.

Keywords:  immune checkpoint inhibitors; immunotherapy; resistance

DOI:  https://doi.org/10.3390/cancers14153575
J Gene Med. 2022 Jul 28. e3443

Bone Marrow Overexpression of SNAI1 is an early indicator of intrinsic drug resistance in patients with De Novo acute myeloid leukemia.

Mahmoud B Y Gouda, Naglaa M Hassan, Eman I Kandil.

   BACKGROUND: The effectiveness of Acute myeloid leukemia (AML) treatment remains a big challenge and resembles a principal cause of AML-related mortality due to chemotherapy resistance. SNAI1 was proved as a leading factor of drug resistance in many cancer types. However, its relation to chemoresistance in AML is not well understood.
METHODS: In addition to standard lab work, the expression level of SNAI1 was determined in bone marrow samples of 109 adult and pediatric patients with De Novo acute myeloid leukemia using RT-qPCR. The relation between SNAI1 and AML drug resistance and immune-modulatory genes was investigated by STRING tool.
RESULTS: SNAI1 expression level was upregulated in AML patients against control cases. In treatment response, SNAI1 showed to be significantly high in resistant patients in comparison to the complete remission (CR) group. SNAI1 overexpression was associated with high initial blasts and total leukocyte counts, but with HLA class II histocompatibility antigen DR (HLA-DR) downregulation. STRING analysis showed that multiple drug resistance and immune-modulatory genes of AML induce SNAI upregulation and activation. Kaplan-Meier analysis indicated that there was no relation between SNAI1 expression level and patients' survival status.
CONCLUSION: We conclude that SNAI1 expression level may be a predictor of intrinsic drug resistance incidence in AML patients.

Keywords:  Acute myeloid leukemia (AML); Drug resistance; HLA class II histocompatibility antigen DR (HLA-DR); Immune suppression; Promyelocytic leukemia (APL, AML-M3); Zinc finger protein SNAI1

DOI:  https://doi.org/10.1002/jgm.3443
Int J Mol Sci. 2022 Jul 17. pii: 7881. [Epub ahead of print]23(14):

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.

Margarita Kobyakova, Yana Lomovskaya, Anatoly Senotov, Alexey Lomovsky, Vladislav Minaychev, Irina Fadeeva, Daria Shtatnova, Kirill Krasnov, Alena Zvyagina, Irina Odinokova, Vladimir Akatov, Roman Fadeev.

  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.

Keywords:  DNA-damaging drugs; acute myeloid leukemia; drug resistance; high-density cell culture; inflammation; izTRAIL

DOI:  https://doi.org/10.3390/ijms23147881