bims-almceb 2022-11-27 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–11–27
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Regulation of hematopoietic and leukemia stem cells by regulatory T cells.
Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?
Acetyl-CoA regulates lipid metabolism and histone acetylation modification in cancer.
CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages.
Editorial: Sphingolipid metabolism and cancer.
Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function.
Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment.
The Growing Role of the BH3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia.
Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade.
TIM-3: a tumor-associated antigen beyond checkpoint inhibition?
Moving towards individualized target-based therapies in acute myeloid leukemia.

Front Immunol. 2022 ;13 1049301

Regulation of hematopoietic and leukemia stem cells by regulatory T cells.

Carsten Riether.

  Adult bone marrow (BM) hematopoietic stem cells (HSCs) are maintained in a quiescent state and sustain the continuous production of all types of blood cells. HSCs reside in a specialized microenvironment the so-called HSC niche, which equally promotes HSC self-renewal and differentiation to ensure the integrity of the HSC pool throughout life and to replenish hematopoietic cells after acute injury, infection or anemia. The processes of HSC self-renewal and differentiation are tightly controlled and are in great part regulated through cellular interactions with classical (e.g. mesenchymal stromal cells) and non-classical niche cells (e.g. immune cells). In myeloid leukemia, some of these regulatory mechanisms that evolved to maintain HSCs, to protect them from exhaustion and immune destruction and to minimize the risk of malignant transformation are hijacked/disrupted by leukemia stem cells (LSCs), the malignant counterpart of HSCs, to promote disease progression as well as resistance to therapy and immune control. CD4+ regulatory T cells (Tregs) are substantially enriched in the BM compared to other secondary lymphoid organs and are crucially involved in the establishment of an immune privileged niche to maintain HSC quiescence and to protect HSC integrity. In leukemia, Tregs frequencies in the BM even increase. Studies in mice and humans identified the accumulation of Tregs as a major immune-regulatory mechanism. As cure of leukemia implies the elimination of LSCs, the understanding of these immune-regulatory processes may be of particular importance for the development of future treatments of leukemia as targeting major immune escape mechanisms which revolutionized the treatment of solid tumors such as the blockade of the inhibitory checkpoint receptor programmed cell death protein 1 (PD-1) seems less efficacious in the treatment of leukemia. This review will summarize recent findings on the mechanisms by which Tregs regulate stem cells and adaptive immune cells in the BM during homeostasis and in leukemia.

Keywords:  hematopoietic stem cell; hematopoietic stem cell niche; immune escape; leukemia stem cell (LSC); regulatory T cell (Treg)

DOI:  https://doi.org/10.3389/fimmu.2022.1049301
Cancers (Basel). 2022 Nov 17. pii: 5655. [Epub ahead of print]14(22):

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

Ziting Zhang, Kun Yang, Han Zhang.

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of hematological malignancy characterized by its high heterogeneity and potentially life-threatening clinical features. Despite the advances in risk stratification and therapeutic management of T-ALL, patients often suffer from treatment failure and chemotherapy-induced toxicity, calling for greater efforts to improve therapeutic efficacy and safety in the treatment of T-ALL. During the past decades, increasing evidence has shown the indispensable effects of leukemia-initiating cells (LICs) and leukemic niches on T-ALL initiation and progression. These milestones greatly facilitate precision medicine by interfering with the pathways that are associated with LICs and leukemic niches or by targeting themselves directly. Most of these novel agents, either alone or in combination with conventional chemotherapy, have shown promising preclinical results, facilitating them to be further evaluated under clinical trials. In this review, we summarize the latest discoveries in LICs and leukemic niches in terms of T-ALL, with a particular highlight on the current precision medicine. The challenges and future prospects are also discussed.

Keywords:  T-cell acute lymphoblastic leukemia; leukemia-initiating cell; leukemic niche; microenvironment; monoclonal antibody; precision medicine; small-molecule inhibitor

DOI:  https://doi.org/10.3390/cancers14225655
Biochim Biophys Acta Rev Cancer. 2022 Nov 17. pii: S0304-419X(22)00162-7. [Epub ahead of print]1878(1): 188837

Acetyl-CoA regulates lipid metabolism and histone acetylation modification in cancer.

Weijing He, Qingguo Li, Xinxiang Li.

  Acetyl-CoA, as an important molecule, not only participates in multiple intracellular metabolic reactions, but also affects the post-translational modification of proteins, playing a key role in the metabolic activity and epigenetic inheritance of cells. Cancer cells require extensive lipid metabolism to fuel for their growth, while also require histone acetylation modifications to increase the expression of cancer-promoting genes. As a raw material for de novo lipid synthesis and histone acetylation, acetyl-CoA has a major impact on lipid metabolism and histone acetylation in cancer. More importantly, in cancer, acetyl-CoA connects lipid metabolism with histone acetylation, forming a more complex regulatory mechanism that influences cancer growth, proliferation, metastasis.

Keywords:  Acetyl-coenzyme A (acetyl-CoA); Cancer; Histone acetylation; Lipid metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2022.188837
Cells. 2022 Nov 10. pii: 3556. [Epub ahead of print]11(22):

CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages.

Noorzaileen Eileena Zaidi, Nur Aima Hafiza Shazali, Thean-Chor Leow, Mohd Azuraidi Osman, Kamariah Ibrahim, Wan-Hee Cheng, Kok-Song Lai, Nik Mohd Afizan Nik Abd Rahman.

  Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer-macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis.

Keywords:  CD36; macrophage; metabolism; metastasis; tumour microenvironment

DOI:  https://doi.org/10.3390/cells11223556
Front Oncol. 2022 ;12 1049494

Editorial: Sphingolipid metabolism and cancer.

Margarita M Ivanova, Irina U Agoulnik, Matilde E LLeonart.



Keywords:  anticancer therapy; cancer; ceramide; metabolism; sphingolipid

DOI:  https://doi.org/10.3389/fonc.2022.1049494
Int J Mol Sci. 2022 Nov 10. pii: 13880. [Epub ahead of print]23(22):

Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function.

Shuting Guan, Li Zhao, Ruiyun Peng.

  Mitochondrial oxidative phospho rylation, the center of cellular metabolism, is pivotal for the energy production in eukaryotes. Mitochondrial oxidative phosphorylation relies on the mitochondrial respiratory chain, which consists of four main enzyme complexes and two mobile electron carriers. Mitochondrial enzyme complexes also assemble into respiratory chain supercomplexes (SCs) through specific interactions. The SCs not only have respiratory functions but also improve the efficiency of electron transfer and reduce the production of reactive oxygen species (ROS). Impaired assembly of SCs is closely related to various diseases, especially neurodegenerative diseases. Therefore, SCs play important roles in improving the efficiency of the mitochondrial respiratory chain, as well as maintaining the homeostasis of cellular metabolism. Here, we review the structure, assembly, and functions of SCs, as well as the relationship between mitochondrial SCs and diseases.

Keywords:  assembly; cytochrome c; mitochondria; respiratory chain; supercomplexes

DOI:  https://doi.org/10.3390/ijms232213880
Biomedicines. 2022 Nov 21. pii: 2988. [Epub ahead of print]10(11):

Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment.

Ethan J Kilmister, Sabrina P Koh, Freya R Weth, Clint Gray, Swee T Tan.

  Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)-a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/β-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a 'silver-bullet' single-target approach.

Keywords:  cancer stem cell; metastasis; renin-angiotensin system; treatment resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines10112988
Mediterr J Hematol Infect Dis. 2022 ;14(1): e2022080

The Growing Role of the BH3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia.

Elvira Pelosi, Germana Castelli, Ugo Testa.

  Despite recent progress, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in the therapy of Venetoclax (VEN), a potent BH3 mimetic targeting the antiapoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed, and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacitidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2, and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes, and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients, the responses have only a limited duration, and the development of resistance is frequently observed. Therefore, understanding the resistance mechanisms is crucial for developing new strategies and identifying rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy), and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3-mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.

Keywords:  Acute myeloid leukemia; BH3

DOI:  https://doi.org/10.4084/MJHID.2022.080
Cells. 2022 Nov 08. pii: 3534. [Epub ahead of print]11(22):

Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade.

Fateme Safaeifard, Bahram Goliaei, Amir R Aref, Mohammad-Hadi Foroughmand-Araabi, Sama Goliaei, Jochen Lorch, Russell W Jenkins, David A Barbie, Seyed Peyman Shariatpanahi, Curzio Rüegg.

  Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two clinically relevant targets for the immunotherapy of cancer, are negative regulators of T-cell activation and migration. Optimizing the therapeutic response to CTLA-4 and PD-1 blockade calls for a more comprehensive insight into the coordinated function of these immune regulators. Mathematical modeling can be used to elucidate nonlinear tumor-immune interactions and highlight the underlying mechanisms to tackle the problem. Here, we investigated and statistically characterized the dynamics of T-cell migration as a measure of the functional response to these pathways. We used a previously developed three-dimensional organotypic culture of patient-derived tumor spheroids treated with anti-CTLA-4 and anti-PD-1 antibodies for this purpose. Experiment-based dynamical modeling revealed the delayed kinetics of PD-1 activation, which originates from the distinct characteristics of PD-1 and CTLA-4 regulation, and followed through with the modification of their contributions to immune modulation. The simulation results show good agreement with the tumor cell reduction and active immune cell count in each experiment. Our findings demonstrate that while PD-1 activation provokes a more exhaustive intracellular cascade within a mature tumor environment, the time-delayed kinetics of PD-1 activation outweighs its preeminence at the individual cell level and consequently confers a functional dominance to the CTLA-4 checkpoint. The proposed model explains the distinct immunostimulatory pattern of PD-1 and CTLA-4 blockade based on mechanisms involved in the regulation of their expression and may be useful for planning effective treatment schemes targeting PD-1 and CTLA-4 functions.

Keywords:  T-cell migration; delayed dynamics; heterogeneous random walks; immune checkpoint blockade; organotypic tumor culture; tumor–immune interaction

DOI:  https://doi.org/10.3390/cells11223534
Immunother Adv. 2022 ;2(1): ltac021

TIM-3: a tumor-associated antigen beyond checkpoint inhibition?

Stefan Barth, Krupa Naran.

  Immune checkpoint inhibitors are one of the most remarkable immunomodulatory therapies of current times. Sabatolimab is a high-affinity, humanized anti-TIM-3 monoclonal antibody currently in development for patients with myeloproliferative disorders, including acute myeloid leukemia and myelodysplastic syndromes. By targeting TIM-3, a receptor expressed on various immune effector cells as well as myeloid cells, multiple mechanisms of action that are distinct from canonical immune checkpoint inhibitors are in play - (i) blockade of TIM-3 and its ligands PtdSer/galectin-9, (ii) modulation of leukemic cell self-renewal as well as (iii) antibody-dependent phagocytosis of TIM-3-expressing leukemic cells. Novel immunotherapies such as sabatolimab which enhance the antitumor immune response on converging fronts represent the promise of a continuously replenished armoury for the treatment of cancer.

Keywords:  TIM-3; antigen; checkpoint; inhibition; tumor-associated

DOI:  https://doi.org/10.1093/immadv/ltac021
Ann Oncol. 2022 Nov 21. pii: S0923-7534(22)04734-2. [Epub ahead of print]

Moving towards individualized target-based therapies in acute myeloid leukemia.

A Bazinet, H M Kantarjian.

  Acute myeloid leukemia (AML) is a heterogeneous disease at the genetic level. The field of AML therapy is increasingly shifting away from uniform approaches based solely on intensive chemotherapy (such as "7 + 3") towards personalized therapy. The treatment of AML can now be individualized based on patient characteristics and cytogenetic/molecular disease features. In this review, we provide a comprehensive updated summary of personalized, target-directed therapy in AML. We first discuss the selection of intensive versus low-intensity treatment approaches based on patient age and/or comorbidities. We follow with a detailed review of specific molecularly-defined AML subtypes that benefit from the addition of targeted agents. In this context, we highlight the urgent need for novel therapies in TP53-mutated AML. We then propose approaches to optimize AML therapy in patients without directly actionable mutations. We conclude with a discussion on the emerging role of using measurable residual disease (MRD) to modify therapy based on the quality of response.

Keywords:  Acute myeloid leukemia; low-intensity therapy; measurable residual disease; personalized therapy; targeted therapy

DOI:  https://doi.org/10.1016/j.annonc.2022.11.004