bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–06–05
thirteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Acute myeloid leukemia: therapeutic targeting of stem cells.
  2. Novel Insights on Lipid Metabolism Alterations in Drug Resistance in Cancer.
  3. Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer.
  4. Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications.
  5. Targeting lipid metabolism in the treatment of ovarian cancer.
  6. Prognostic utility of key copy number alterations in T cell acute lymphoblastic leukemia.
  7. Integrative understanding of immune-metabolic interaction.
  8. Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.
  9. Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers.
  10. Immune Cell Metabolic Fitness for Life.
  11. Deacetylation of YAP1 Promotes the Resistance to Chemo- and Targeted Therapy in FLT3-ITD+ AML Cells.
  12. Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
  13. The Mitochondrial Pyruvate Carrier at the Crossroads of Intermediary Metabolism.
  1. Expert Opin Ther Targets. 2022 Jun 02. 1-10
    Acute myeloid leukemia: therapeutic targeting of stem cells.
    Cindy M Pabon, Hussein A Abbas, Marina Konopleva.
       INTRODUCTION: Despite advances in the treatment of acute myeloid leukemia (AML), long-term survival remains low. In 1994, it was proposed that leukemic stem cells (LSCs) played a key role in relapsed and refractory disease. LSCs are capable of self-renewal, proliferation, differentiation, immune evasion, and drug resistance through several unique mechanisms. More recent leukemia drug development initiatives have included efforts to target LSCs. With LSCs, the challenge with such drug design is finding a way to selectively target LSCs while sparing normal hematopoietic stem cells (HSCs).
    AREAS COVERED: In this review, we explore the evolving knowledge of the unique LSC biology and physiology in the scientific literature, while noting the several agents that have been designed throughout the years to target this subgroup of leukemic cells. Our review includes discussion on chimeric antigen receptor T cells, monoclonal antibodies, antibody-drug conjugates against cell surface markers, signaling pathway targets, pro-apoptotic agents, epigenetic regulators, and more.
    EXPERT OPINION: As our understanding of the intricate pathophysiology of LSCs continues to grow, it is clear that targeting such heterogenous cells successfully will require a thoughtful and multi-modal approach.
    Keywords:  Leukemic stem cell; acute myeloid leukemia; hematopoiesis; targeted therapy
    DOI:  https://doi.org/10.1080/14728222.2022.2083957
  2. Front Cell Dev Biol. 2022 ;10 875318
    Novel Insights on Lipid Metabolism Alterations in Drug Resistance in Cancer.
    Ruixue Yang, Mei Yi, Bo Xiang.
      Chemotherapy is one of the primary treatments for most human cancers. Despite great progress in cancer therapeutics, chemotherapy continues to be important for improving the survival of cancer patients, especially for those who has unresectable metastatic tumors or fail to respond to immunotherapy. However, intrinsic or acquired chemoresistance results in tumor recurrence, which remains a major obstacle in anti-cancer treatment. The high prevalence of chemoresistant cancer makes it urgent to deepen our understanding on chemoresistance mechanisms and to develop novel therapeutic strategies. Multiple mechanisms, including drug efflux, enhanced DNA damage reparability, increased detoxifying enzymes levels, presence of cancer stem cells (CSCs), epithelial mesenchymal transition (EMT), autophagy, ferroptosis and resistance to apoptosis, underlie the development of chemoresistance. Recently, accumulating evidence suggests that lipid metabolism alteration is closely related to drug resistance in tumor. Targeting lipid metabolism in combination with traditional chemotherapeutic drugs is a promising strategy to overcome drug resistance. Therefore, this review compiles the current knowledge about aberrant lipid metabolism in chemoresistant cancer, mainly focusing on aberrant fatty acid metabolism, and presents novel therapeutic strategies targeting altered lipid metabolism to overcome chemoresistance in cancer.
    Keywords:  Cancer chemoresistance; drug resistance; fatty acid metabolism; lipid metabolism; multi-drug resistance
    DOI:  https://doi.org/10.3389/fcell.2022.875318
  3. J Transl Med. 2022 May 31. 20(1): 246
    Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer.
    Shruthi Sriramkumar, Riddhi Sood, Thomas D Huntington, Ahmed H Ghobashi, Truc T Vuong, Tara X Metcalfe, Weini Wang, Kenneth P Nephew, Heather M O'Hagan.
       BACKGROUND: Platinum based agents-cisplatin and carboplatin in combination with taxanes are used for the treatment of ovarian cancer (OC) patients. However, the majority of OC patients develop recurrent, platinum resistant disease that is uniformly fatal. Platinum treatment enriches for chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSCs), which contribute to tumor recurrence and disease relapse. Acquired platinum resistance also includes metabolic reprograming and switching to oxidative phosphorylation (OXPHOS). Chemosensitive cells rely on glycolysis while chemoresistant cells have the ability to switch between glycolysis and OXPHOS, depending on which pathway drives a selective advantage for growth and chemoresistance. High expression of genes involved in OXPHOS and high production of mitochondrial ROS are characteristics of OCSCs, suggesting that OCSCs favor OXPHOS over glycolysis. Based on connections between OCSCs, chemoresistance and OXPHOS, we hypothesize that platinum treatment induces changes in metabolism that contribute to platinum-induced enrichment of OCSCs.
    METHODS: The effect of cisplatin on mitochondrial activity was assessed by JC1 staining and expression of OXPHOS genes by RT-qPCR. Cisplatin-induced changes in Sirtuin 1 (SIRT1) levels and activity were assessed by western blot. Small molecule inhibitors of mitochondrial complex I and SIRT1 were used to determine if their enzymatic activity contributes to the platinum-induced enrichment of OCSCs. The percentage of ALDH + OCSCs in OC cells and tumor tissue from xenograft models across different treatment conditions was analyzed using ALDEFLUOR assay and flow cytometry.
    RESULTS: We demonstrate that platinum treatment increases mitochondrial activity. Combined treatment of platinum agents and OXPHOS inhibitors blocks the platinum-induced enrichment of ALDH + OCSCs in vitro and in vivo. Furthermore, platinum treatment increases SIRT1 levels and subsequent deacetylase activity, which likely contributes to the increase in platinum-induced mitochondrial activity.
    CONCLUSIONS: These findings on metabolic pathways altered by platinum-based chemotherapy have uncovered key targets that can be exploited therapeutically to block the platinum-induced enrichment of OCSCs, ultimately improving the survival of OC patients.
    Keywords:  ALDH + cells; Cancer stem cells; Chemoresistance; OXPHOS; Ovarian cancer; Platinum; SIRT1
    DOI:  https://doi.org/10.1186/s12967-022-03447-y
  4. Cytokine. 2022 May 26. pii: S1043-4666(22)00125-9. [Epub ahead of print]156 155916
    Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications.
    Mushtaq Ahmad Nengroo, Ayushi Verma, Dipak Datta.
      A subpopulation of cells in many cancers has stem cell traits, mediates metastasis, and contributes to treatment resistance. These cells are considered as cancer stem cells (CSCs). CSC properties of tumor cells are immensely regulated by close interactions with tumor microenvironment components such as mesenchymal stem cells, tumor related fibroblasts, adipocytes, endothelial cells, and immune cells via the intricate network of cytokines, chemokines, and growth factors. Inflammatory cytokines including interleukin (IL)-1, IL-6, and IL-8 play a major role in these interactions via the activation of signal transduction pathways like Stat3/NF-κB etc. in stromal and tumor cells. The activation of these pathways increases the release of more cytokines, resulting in positive feedback loops which help in CSC self-renewal. The pathways controlled by these cytokine loops are similar to those that are active during chronic inflammation and wound healing, suggesting that they might have critical role in establishing relationship between inflammation and cancer. Anti-inflammatory drugs have been identified to inhibit these cytokines and their receptor mediated pathways. These agents have the potential to target CSCs by inhibiting signals from the tumor microenvironment and considered to be a potential candidate for future therapeutics. The significance of cytokines released from the tumor microenvironment in different phases of cancer, as well as their potential application in cancer therapeutics is discussed in this article.
    Keywords:  Cancer stem cells; Cytokines; Immunotherapeutics; Inflammation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cyto.2022.155916
  5. Oncotarget. 2022 ;13 768-783
    Targeting lipid metabolism in the treatment of ovarian cancer.
    Saliha Chaudhry, Stefani N Thomas, Glenn E Simmons.
      Cancer cells undergo alterations in lipid metabolism to support their high energy needs, tumorigenesis and evade an anti-tumor immune response. Alterations in fatty acid production are controlled by multiple enzymes, chiefly Acetyl CoA Carboxylase, ATP-Citrate Lyase, Fatty Acid Synthase, and Stearoyl CoA Desaturase 1. Ovarian cancer (OC) is a common gynecological malignancy with a high rate of aggressive carcinoma progression and drug resistance. The accumulation of unsaturated fatty acids in ovarian cancer supports cell growth, increased cancer cell migration, and worse patient outcomes. Ovarian cancer cells also expand their lipid stores via increased uptake of lipids using fatty acid translocases, fatty acid-binding proteins, and low-density lipoprotein receptors. Furthermore, increased lipogenesis and lipid uptake promote chemotherapy resistance and dampen the adaptive immune response needed to eliminate tumors. In this review, we discuss the role of lipid synthesis and metabolism in driving tumorigenesis and drug resistance in ovarian cancer conferring poor prognosis and outcomes in patients. We also cover some aspects of how lipids fuel ovarian cancer stem cells, and how these metabolic alterations in intracellular lipid content could potentially serve as biomarkers of ovarian cancer.
    Keywords:  biomarkers; fatty acid; lipid metabolism; microenvironment; ovarian cancer
    DOI:  https://doi.org/10.18632/oncotarget.28241
  6. Hematol Oncol. 2022 May 29.
    Prognostic utility of key copy number alterations in T cell acute lymphoblastic leukemia.
    Sarita Kumari, Md Shadab Ali, Jay Singh, Mohit Arora, Deepak Verma, Avanish Kumar Pandey, Mercilena Benjamin, Sameer Bakhshi, Jayanth Kumar Palanichamy, Atul Sharma, Inder Singh, Pranay Tanwar, Amar Ranjan Singh, Deepam Pushpam, Imteyaz Qamar, Anita Chopra.
      T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, characterized by an abnormal transformation of T cells into highly proliferative leukemic lymphoblasts. Identification of common genetic alterations has provided promising opportunities for better risk stratification in T-ALL. Current treatment in T-ALL still poses the major challenge of integrating the knowledge of molecular alterations in the clinical setting. We utilized the Multiplex Ligation Dependent Probe Amplification (MLPA) method to determine the frequency of common copy number alterations (CNA) in 128 newly diagnosed T-ALL patients. We also studied the association of these CNAs with patient's clinical characteristics and survival. The highest frequency of deletion was observed in CDKN2A (59.38%), followed by CDKN2B (46.88%), LMO1 (37.5%), and MTAP (28.12%). PTPN2 (22.66%), PHF6 (14.06%), and MYB (14.06%) had the highest number of duplication events. A total of 89.06% patients exhibited CNAs. STIL::TAL1, NUP214::ABL1, and LMO2::RAG2 fusions were observed in 5.47%, 3.12%, and 0.78% of patients, respectively. CDKN2A, CDKN2B, and PTPN2 gene deletions were mainly observed in pediatric patients, while CNAs of NF1 and SUZ12 were observed more frequently in adults. In pediatric patients, alterations in CDKN2B, CASP8AP2, and AHI1 were associated with poor prognosis, while SUZ12 and NF1 CNAs were associated with favorable prognosis. In adult patients, ABL1 CNA emerged as an independent indicator of poor prognosis. The observed molecular heterogeneity in T-ALL may provide the basis for variations observed in clinical response in T-ALL and MLPA based CNA detection may help in risk stratification of these patients. This article is protected by copyright. All rights reserved.
    Keywords:  CDKN2A/B; Leukemia; MLPA; T-ALL; copy number alterations
    DOI:  https://doi.org/10.1002/hon.3030
  7. BMB Rep. 2022 Jun 02. pii: 5619. [Epub ahead of print]
    Integrative understanding of immune-metabolic interaction.
    Seonyoung Lim, Hawon Kim, Myunghyun Jeong, Hyeon Yang, Jun Young Hong.
      Recent studies have revealed that the immune system plays a critical role in various physiological processes beyond its classical pathogen control activity. Even under a sterile condition, various cells and tissues can utilize the immune system to meet a specific demand for proper physiological functions. Particularly, a strong link between immunity and metabolism has been identified. Studies have identified the reciprocal regulation between these two systems. For example, immune signals can regulate metabolism, and metabolism (cellular or systemic) can regulate immunity. In this review, we will summarize recent findings on this reciprocal regulation between immunity and metabolism, and discuss potential biological rules behind this interaction with integrative perspectives.
  8. Front Cell Dev Biol. 2022 ;10 808859
    Tumor-Derived Lactate Creates a Favorable Niche for Tumor via Supplying Energy Source for Tumor and Modulating the Tumor Microenvironment.
    Mengyao Jin, Wei Cao, Bo Chen, Maoming Xiong, Guodong Cao.
      Tumor evolution is influenced by events involving tumor cells and the environment in which they live, known as the tumor microenvironment (TME). TME is a functional and structural niche composed of tumor cells, endothelial cells (ECs), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), and a subset of immune cells (macrophages, dendritic cells, natural killer cells, T cells, B cells). Otto Warburg revealed the Warburg effect in 1923, a characteristic metabolic mechanism of tumor cells that performs high glucose uptake and excessive lactate formation even in abundant oxygen. Tumor tissues excrete a large amount of lactate into the extracellular microenvironment in response to TME's hypoxic or semi-hypoxic state. High lactate concentrations in tumor biopsies have been linked to metastasis and poor clinical outcome. This indicates that the metabolite may play a role in carcinogenesis and lead to immune escape in TME. Lactate is now recognized as an essential carbon source for cellular metabolism and as a signaling molecule in TME, forming an active niche that influences tumor progression. This review summarized the advanced literature demonstrating the functional role of lactate in TME remodeling, elucidating how lactate shapes the behavior and the phenotype of both tumor cells and tumor-associated cells. We also concluded the intriguing interactions of multiple immune cells in TME. Additionally, we demonstrated how lactate functioned as a novel function factor by being used in a new histone modification, histone lysine lactylation, and to regulate gene expression in TME. Ultimately, because lactate created a favorable niche for tumor progression, we summarized potential anti-tumor strategies targeting lactate metabolism and signaling to investigate better cancer treatment.
    Keywords:  energy source; immune response; lactate; lactylation; tumor micoenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.808859
  9. Biochem Pharmacol. 2022 May 28. pii: S0006-2952(22)00204-0. [Epub ahead of print] 115110
    Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers.
    Libo Xu, Jinghua Zhang, Jicheng Sun, Kunlin Hou, Chenxin Yang, Ying Guo, Xiaorui Liu, Dhan V Kalvakolanu, Ling Zhang, Baofeng Guo.
      The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.
    Keywords:  autophagy; cancer stem cells; drug resistance; epigenetics; quiescence; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.bcp.2022.115110
  10. Antibodies (Basel). 2022 Apr 30. pii: 32. [Epub ahead of print]11(2):
    Immune Cell Metabolic Fitness for Life.
    Kevin S Bittman.
      Adoptive cell therapy holds great promise for treating a myriad of diseases, especially cancer. Within the last decade, immunotherapy has provided a significant leap in the successful treatment of leukemia. The research conducted throughout this period to understand the interrelationships between cancer cells and infiltrating immune cells winds up having one very common feature, bioenergetics. Cancer cells and immune cells both need ATP to perform their individual functions and cancer cells have adopted means to limit immune cell activity via changes in immune cell bioenergetics that redirect immune cell behavior to encourage tumor growth. Current leading strategies for cancer treatment super-charge an individual's own immune cells against cancer. Successful Chimeric Antigen Receptor T Cells (CAR T) target pathways that ultimately influence bioenergetics. In the last decade, scientists identified that mitochondria play a crucial role in T cell physiology. When modifying T cells to create chimeras, a unique mitochondrial fitness emerges that establishes stemness and persistence. This review highlights many of the key findings leading to this generation's CAR T treatments and the work currently being done to advance immunotherapy, to empower not just T cells but other immune cells as well against a variety of cancers.
    Keywords:  CAR T; bioenergetics; immunotherapy; metabolism
    DOI:  https://doi.org/10.3390/antib11020032
  11. Front Cell Dev Biol. 2022 ;10 842214
    Deacetylation of YAP1 Promotes the Resistance to Chemo- and Targeted Therapy in FLT3-ITD+ AML Cells.
    Panpan Feng, Jingru Zhang, Juan Zhang, Xiaomin Liu, Lina Pan, Dawei Chen, Min Ji, Fei Lu, Peng Li, Guosheng Li, Tao Sun, Jingxin Li, Jingjing Ye, Chunyan Ji.
      The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cell resistance to chemo- and targeted therapy. Mass spectrometric assay revealed that DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown was partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage, and significantly attenuated FLT3-ITD+ AML cell resistance. In addition, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+ AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients.
    Keywords:  FLT3-ITD+ AML; HDAC10; PARP1; Yap1; resistance
    DOI:  https://doi.org/10.3389/fcell.2022.842214
  12. Cell Rep. 2022 May 31. pii: S2211-1247(22)00645-3. [Epub ahead of print]39(9): 110870
    Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
    Yi-Jia Li, Johannes Francois Fahrmann, Maryam Aftabizadeh, Qianqian Zhao, Satyendra C Tripathi, Chunyan Zhang, Yuan Yuan, David Ann, Samir Hanash, Hua Yu.
      Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.
    Keywords:  ACSL; CP: Cancer; CP: Metabolism; STAT3 acetylation; anti-apoptosis; chemoresistance; fatty acid oxidation; mitochondrial membrane potential; phospholipids
    DOI:  https://doi.org/10.1016/j.celrep.2022.110870
  13. Am J Physiol Endocrinol Metab. 2022 May 30.
    The Mitochondrial Pyruvate Carrier at the Crossroads of Intermediary Metabolism.
    Nicole K H Yiew, Brian N Finck.
      Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily-conserved process and aberrant pyruvate metabolism is associated with and contributes to numerous human metabolic disorders including diabetes, cancer, and heart disease. As a product of glycolysis, pyruvate is primarily generated in the cytosol before being transported into the mitochondrion for further metabolism. Pyruvate entry into the mitochondrial matrix is a critical step for efficient generation of reducing equivalents and ATP and for the biosynthesis of glucose, fatty acids, and amino acids from pyruvate. However, for many years the identity of the carrier protein(s) that transported pyruvate into the mitochondrial matrix remained a mystery. In 2012, the molecular-genetic identification of the mitochondrial pyruvate carrier (MPC), a heterodimeric complex composed of protein subunits MPC1 and MPC2, enabled studies that shed light on the many metabolic and physiologic processes regulated by pyruvate metabolism. A better understanding of the mechanisms regulating pyruvate transport and the processes affected by pyruvate metabolism may enable novel therapeutics to modulate mitochondrial pyruvate flux to treat a variety disorders. Herein, we review our current knowledge of the MPC, discuss recent advances in the understanding of mitochondrial pyruvate metabolism in various tissue and cell types, and address some of the outstanding questions relevant to this field.
    Keywords:  adipose tissue; heart; liver; mitochondrion; pyruvate
    DOI:  https://doi.org/10.1152/ajpendo.00074.2022
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