bims-almceb 2022-09-18 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–09–18
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters.
An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia.
A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy.
Characteristics and prognosis of children with recurrent T-cell acute lymphoblastic leukemia: a long-term follow-up report in China.
Signatures of immune dysfunction predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia.
Metabolic reprogramming in the OPA1-deficient cells.
Metabolic plasticity and regulation of T cell exhaustion.
100 years of the Warburg effect: a historical perspective.
Sorting-free metabolic profiling uncovers the vulnerability of fatty acid β-oxidation in in vitro quiescence models.

iScience. 2022 Sep 16. 25(9): 105013

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters.

Noortje van Gils, Han J M P Verhagen, Michaël Broux, Tania Martiáñez, Fedor Denkers, Eline Vermue, Arjo Rutten, Tamás Csikós, Sofie Demeyer, Meryem Çil, Marjon Al, Jan Cools, Jeroen J W M Janssen, Gert J Ossenkoppele, Renee X Menezes, Linda Smit.

  Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells (measurable residual disease; MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing histone 3 lysine 27 (H3K27) and H3K4 tri-methylation. Within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking doxorubicin-induced H3K27me3 or H3K4me3 upregulation. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by KDM6 inhibition. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced chemotherapy response in vivo. Our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells.

Keywords:  Cancer; Molecular biology; Therapy

DOI:  https://doi.org/10.1016/j.isci.2022.105013
PLoS Comput Biol. 2022 Sep;18(9): e1010439

An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia.

Michelle Przedborski, David Sharon, Severine Cathelin, Steven Chan, Mohammad Kohandel.

The over-expression of the Bcl-2 protein is a common feature of many solid cancers and hematological malignancies, and it is typically associated with poor prognosis and resistance to chemotherapy. Bcl-2-specific inhibitors, such as venetoclax, have recently been approved for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and they are showing promise in clinical trials as a targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML). However, successful treatment of AML with Bcl-2-specific inhibitors is often followed by the rapid development of drug resistance. An emerging paradigm for overcoming drug resistance in cancer treatment is through the targeting of mitochondrial energetics and metabolism. In AML in particular, it was recently observed that inhibition of mitochondrial translation via administration of the antibiotic tedizolid significantly affects mitochondrial bioenergetics, activating the integrated stress response (ISR) and subsequently sensitizing drug-resistant AML cells to venetoclax. Here we develop an integrative systems biology approach to acquire a deeper understanding of the molecular mechanisms behind this process, and in particular, of the specific role of the ISR in the commitment of cells to apoptosis. Our multi-scale mathematical model couples the ISR to the intrinsic apoptosis pathway in venetoclax-resistant AML cells, includes the metabolic effects of treatment, and integrates RNA, protein level, and cellular viability data. Using the mathematical model, we identify the dominant mechanisms by which ISR activation helps to overcome venetoclax resistance, and we study the temporal sequencing of combination treatment to determine the most efficient and robust combination treatment protocol.

DOI: https://doi.org/10.1371/journal.pcbi.1010439
Front Oncol. 2022 ;12 962928

A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.

Eric A Hanse, Mei Kong.

  A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.

Keywords:  alpha ketoglutarate; epigenetics; glutamine; glutaminolysis-inhibition; metabolism; tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.962928
Front Oncol. 2022 ;12 987499

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy.

Leqiang Zhang, Ning Chang, Jia Liu, Zhuojun Liu, Yajin Wu, Linlin Sui, Wei Chen.

  Hematological malignancies are one of the most lethal illnesses that seriously threaten human life and health. Lipids are important constituents of various biological membranes and substances for energy storage and cell signaling. Furthermore, lipids are critical in the normal physiological activities of cells. In the process of the lethal transformation of hematological malignancies, lipid metabolism reprogramming meets the material and energy requirements of rapidly proliferating and dividing tumor cells. A large number of studies have shown that dysregulated lipid metabolism, commonly occurs in hematological malignancies, mediating the proliferation, growth, migration, invasion, apoptosis, drug resistance and immune escape of tumor cells. Targeting the lipid metabolism pathway of hematological malignancies has become an effective therapeutic approach. This article reviews the oncogenic mechanisms of lipid metabolism reprogramming in hematological malignancies, including fatty acid, cholesterol and phospholipid metabolism, thereby offering an insight into targeting lipid metabolism in the treatment of hematological malignancies.

Keywords:  cholesterol; fatty acids; hematological malignancies; lipid metabolism reprogramming; phospholipids

DOI:  https://doi.org/10.3389/fonc.2022.987499
Leuk Lymphoma. 2022 Sep 15. 1-13

Characteristics and prognosis of children with recurrent T-cell acute lymphoblastic leukemia: a long-term follow-up report in China.

Xiaoming Liu, Yao Zou, Li Zhang, Yingchi Zhang, Yumei Chen, Xiaojuan Chen, Ye Guo, Wenyu Yang, Xiaofan Zhu.

  This study assessed the relapse characteristics and prognosis of 145 children newly diagnosed with T-cell acute lymphoblastic leukemia (T-ALL). The overall complete response (CR) rate was 91.7% (133/145), and the overall recurrence rate was 31.6% (42/133). The recurrence rate in the intermediate-risk (IR) group and high-risk (HR) group was 15.4% and 47.1%, respectively (p < 0.001). Patients with young age, early T-cell precursor ALL, central nervous system (CNS) involvement, TCRγ gene rearrangement, karyotypic abnormalities, or absence of TCRβ gene rearrangement (p < 0.05) tended to relapse. All recurrences occurred within 36 months after diagnosis. The HR group recurred earlier than the IR group (p= 0.026). The 3-year overall survival (OS) rate was significantly lower in the HR group than in the IR group (p < 0.001). All relapsed children died within 12 months after recurrence. Early intervention may benefit children with a high risk of recurrence.

Keywords:  Child; T-cell acute lymphoblastic leukemia; long-term follow-up; recurrence

DOI:  https://doi.org/10.1080/10428194.2022.2123224
J Clin Invest. 2022 Sep 13. pii: e159579. [Epub ahead of print]

Signatures of immune dysfunction predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia.

Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik.

   BACKGROUND AND METHODS: The functional and transcriptional features of immune effector senescence and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).
RESULTS: We show that senescent-like bone marrow CD8+ T cells were impaired in killing autologous AML blasts, and that their proportion negatively correlated with overall survival (OS). We defined new immune effector dysfunction (IED) signatures using two gene expression profiling platforms and report that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or leukemia stem cell (LSC17) scores. IED expression signatures also identified an ICB-unresponsive tumor microenvironment and predicted significantly worse OS.
CONCLUSION: The newly described IED scores provided improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.

Keywords:  Cancer immunotherapy; Cellular senescence; Hematology; Leukemias

DOI:  https://doi.org/10.1172/JCI159579
Cell Mol Life Sci. 2022 Sep 14. 79(10): 517

Metabolic reprogramming in the OPA1-deficient cells.

Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.

  OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.

Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation

DOI:  https://doi.org/10.1007/s00018-022-04542-5
Immunology. 2022 Sep 11.

Metabolic plasticity and regulation of T cell exhaustion.

Fei Li, Huiling Liu, Dan Zhang, Yanlin Ma, Bingdong Zhu.

  The metabolic reprogramming during T cell activation and differentiation affects T cell fate and immune responses. Cell metabolism may serve as the driving force that induces epigenetic modifications, contributing to regulating T cell differentiation. Persistent pathogen infection leads to T cell exhaustion, which is composed of two main subsets and with distinct metabolic characteristics. The progenitor exhausted T cells utilize mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) for energy, while terminally exhausted T cells mainly rely on glycolytic metabolism with impaired glycolysis and OXPHOS. Here, we compiled the latest research on how T cell metabolism defines differentiation, focusing on T cell exhaustion during chronic infections. In addition, metabolic-related factors including antigen stimulation signals strength, cytokines and epigenetics affecting T cell exhaustion were also reviewed. Furthermore, the intervention strategies on metabolism and epigenetics to reverse T cell exhaustion were discussed in detail, which may contribute to achieving the goal of prevention and treatment of T cell exhaustion.

Keywords:  Chronic infection; Epigenetics; Glycolysis; T cell exhaustion; T cell metabolism

DOI:  https://doi.org/10.1111/imm.13575
Endocr Relat Cancer. 2022 Sep 01. pii: ERC-22-0173. [Epub ahead of print]

100 years of the Warburg effect: a historical perspective.

David Grahame Hardie.

Otto Warburg published the first papers describing what became known as the Warburg effect in 1923. All that was known about glucose metabolism at that time was that it occurred in two stages: (i) fermentation or glycolysis, in which glucose was converted to lactate, which did not require oxygen, and (ii) oxidative metabolism, in which the carbon atoms derived from glycolysis were fully oxidized to carbon dioxide, which did require oxygen. Warburg discovered that most tumour tissues produced a large amount of lactate that was reduced but not eliminated in the presence of oxygen, while most normal tissues produced a much smaller amount of lactate that was eliminated by provision of oxygen. These findings were clearly well ahead of their time because it was another 80 years before they were to have any major impact, and even today the mechanisms underlying the Warburg effect are not completely understood.

DOI: https://doi.org/10.1530/ERC-22-0173
Mol Syst Biol. 2022 Sep;18(9): e10716

Sorting-free metabolic profiling uncovers the vulnerability of fatty acid β-oxidation in in vitro quiescence models.

Karin Ortmayr, Mattia Zampieri.

  Quiescent cancer cells are rare nondiving cells with the unique ability to evade chemotherapies and resume cell division after treatment. Despite the associated risk of cancer recurrence, how cells can reversibly switch between rapid proliferation and quiescence remains a long-standing open question. By developing a unique methodology for the cell sorting-free separation of metabolic profiles in cell subpopulations in vitro, we unraveled metabolic characteristics of quiescent cells that are largely invariant to basal differences in cell types and quiescence-inducing stimuli. Consistent with our metabolome-based analysis, we show that impairing mitochondrial fatty acid β-oxidation (FAO) can induce apoptosis in quiescence-induced cells and hamper their return to proliferation. Our findings suggest that in addition to mediating energy and redox balance, FAO can play a role in preventing the buildup of toxic intermediates during transitioning to quiescence. Uncovering metabolic strategies to enter, maintain, and exit quiescence can reveal fundamental principles in cell plasticity and new potential therapeutic targets beyond cancer.

Keywords:  cellular quiescence; fatty acid oxidation; metabolic adaptation; quiescence-proliferation transition; trimetazidine

DOI:  https://doi.org/10.15252/msb.202110716