bims-almceb 2021-05-30 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–05–30
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.
Lipid metabolism in focus: how the build-up and breakdown of lipids affects stem cells.
CD38-directed CAR-T cell therapy: a novel immunotherapy strategy for relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.
Immunotherapy in Acute Myeloid Leukemia: Where We Stand.
The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes.
Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis.
Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities.
The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies.
Mechanisms of Cancer Stem Cell Senescence: Current Understanding and Future Perspectives.
Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics.

Blood Cancer Discov. 2021 May;2(3): 266-287

SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.

Dongqing Yan, Anca Franzini, Anthony D Pomicter, Brayden J Halverson, Orlando Antelope, Clinton C Mason, Jonathan M Ahmann, Anna V Senina, Nadeem A Vellore, Courtney L Jones, Matthew S Zabriskie, Hein Than, Michael J Xiao, Alexandria van Scoyk, Ami B Patel, Phillip M Clair, William L Heaton, Shawn C Owen, Joshua L Andersen, Christina M Egbert, Julie A Reisz, Angelo D'Alessandro, James E Cox, Kevin C Gantz, Hannah M Redwine, Siddharth M Iyer, Jamshid S Khorashad, Nima Rajabi, Christian A Olsen, Thomas O'Hare, Michael W Deininger.

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.

DOI: https://doi.org/10.1158/2643-3230.bcd-20-0168
Development. 2021 May 15. pii: dev191924. [Epub ahead of print]148(10):

Lipid metabolism in focus: how the build-up and breakdown of lipids affects stem cells.

Sofia Madsen, Mergim Ramosaj, Marlen Knobloch.

  Cellular metabolism has recently emerged as a key regulator of stem cell behavior. Various studies have suggested that metabolic regulatory mechanisms are conserved in different stem cell niches, suggesting a common level of stem cell regulation across tissues. Although the balance between glycolysis and oxidative phosphorylation has been shown to be distinct in stem cells and their differentiated progeny, much less is known about lipid metabolism in stem cell regulation. In this Review, we focus on how stem cells are affected by two major lipid metabolic pathways: the build-up of lipids, called de novo lipogenesis, and the breakdown of lipids, called fatty acid beta-oxidation. We cover the recent literature on hematopoietic stem cells, intestinal stem cells, neural stem/progenitor cells and cancer stem cells, where these two lipid pathways have been studied in more depth.

Keywords:   De novo lipogenesis; Cancer stem cells; Fatty acid beta-oxidation; Hematopoietic stem cells; Intestinal stem cells; Lipid metabolism; Neural stem/progenitor cells

DOI:  https://doi.org/10.1242/dev.191924
J Hematol Oncol. 2021 May 25. 14(1): 82

CD38-directed CAR-T cell therapy: a novel immunotherapy strategy for relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.

Qingya Cui, Chongsheng Qian, Nan Xu, Liqing Kang, Haiping Dai, Wei Cui, Baoquan Song, Jia Yin, Zheng Li, Xiaming Zhu, Changju Qu, Tianhui Liu, Wenhong Shen, Mingqing Zhu, Lei Yu, Depei Wu, Xiaowen Tang.

  Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). However, most patients experience relapse after allo-HSCT, with a poor prognosis, and treatment options are limited. The lack of an ideal targetable antigen is a major obstacle for treating patients with relapsed AML. CD38 is known to be expressed on most AML and myeloma cells, and its lack of expression on hematopoietic stem cells (HSCs) renders it a potential therapeutic target for relapsed AML. To investigate the clinical therapeutic efficacy and safety of CD38-targeted chimeric antigen receptor T (CAR-T-38) cells, we enrolled 6 AML patients who experienced relapse post-allo-HSCT (clinicaltrials.gov: NCT04351022). Prior to CAR-T-38 treatment, the blasts in the bone marrow of these patients exhibited a median of 95% (92-99%) CD38 positivity. Four weeks after the initial infusion of CAR-T-38 cells, four of six (66.7%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi); the median CR or CRi time was 191 (range 117-261) days. The cumulative relapse rate at 6 months was 50%. The median overall survival (OS) and leukemia-free survival (LFS) times were 7.9 and 6.4 months, respectively. One case relapsed 117 days after the first CAR-T-38 cell infusion, with remission achieved after the second CAR-T-38 cell infusion. All six patients experienced clinically manageable side effects. In addition, multiparameter flow cytometry (FCM) revealed that CAR-T-38 cells eliminated CD38 positive blasts without off-target effects on monocytes and lymphocytes. Although this prospective study has a limited number of cases and a relatively short follow-up time, our preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML post-allo-HSCT.

Keywords:  Allogeneic hematopoietic stem cell transplantation; CAR-T-38; Chimeric antigen receptor T cells; Cytokine release syndrome; Relapsed acute myeloid leukemia

DOI:  https://doi.org/10.1186/s13045-021-01092-4
Front Oncol. 2021 ;11 656218

Immunotherapy in Acute Myeloid Leukemia: Where We Stand.

Alessandro Isidori, Claudio Cerchione, Naval Daver, Courtney DiNardo, Guillermo Garcia-Manero, Marina Konopleva, Elias Jabbour, Farhad Ravandi, Tapan Kadia, Adolfo de la Fuente Burguera, Alessandra Romano, Federica Loscocco, Giuseppe Visani, Giovanni Martinelli, Hagop Kantarjian, Antonio Curti.

  In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade via PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.

Keywords:  acute myeloid leukemia; checkpoint inhibitors; immunotherapy; monoclonal antibody; natural killer; tolerance

DOI:  https://doi.org/10.3389/fonc.2021.656218
Front Mol Biosci. 2021 ;8 671908

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes.

Olga A Zhunina, Nikita G Yabbarov, Andrey V Grechko, Antonina V Starodubova, Ekaterina Ivanova, Nikita G Nikiforov, Alexander N Orekhov.

  Mitochondrial dysfunction is known to be associated with a wide range of human pathologies, such as cancer, metabolic, and cardiovascular diseases. One of the possible ways of mitochondrial involvement in the cellular damage is excessive production of reactive oxygen and nitrogen species (ROS and RNS) that cannot be effectively neutralized by existing antioxidant systems. In mitochondria, ROS and RNS can contribute to protein and mitochondrial DNA (mtDNA) damage causing failure of enzymatic chains and mutations that can impair mitochondrial function. These processes further lead to abnormal cell signaling, premature cell senescence, initiation of inflammation, and apoptosis. Recent studies have identified numerous mtDNA mutations associated with different human pathologies. Some of them result in imbalanced oxidative phosphorylation, while others affect mitochondrial protein synthesis. In this review, we discuss the role of mtDNA mutations in cancer, diabetes, cardiovascular diseases, and atherosclerosis. We provide a list of currently described mtDNA mutations associated with each pathology and discuss the possible future perspective of the research.

Keywords:  DNA damage; atherosclerosis; cancer; diabetes; mitochondria; reactive nitrogen species; reactive oxygen species

DOI:  https://doi.org/10.3389/fmolb.2021.671908
FASEB J. 2021 Jun;35(6): e21620

Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis.

Mary Adebayo, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta.

  Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.

Keywords:  diseases; dynamics; fission; fusion; mitochondria

DOI:  https://doi.org/10.1096/fj.202100067R
Blood Rev. 2021 May 12. pii: S0268-960X(21)00056-4. [Epub ahead of print] 100850

Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities.

Eimear O'Reilly, Hojjat Alizadeh Zeinabad, Eva Szegezdi.

  Hematopoietic stem cells (HSC) are responsible for the production of mature blood cells. To ensure that the HSC pool does not get exhausted over the lifetime of an individual, most HSCs are in a state of quiescence with only a small proportion of HSCs dividing at any one time. HSC quiescence is carefully controlled by both intrinsic and extrinsic, niche-driven mechanisms. In acute myeloid leukemia (AML), the leukemic cells overtake the hematopoietic bone marrow niche where they acquire a quiescent state. These dormant AML cells are resistant to chemotherapeutics. Because they can re-establish the disease after therapy, they are often termed as quiescent leukemic stem cells (LSC) or leukemia-initiating cells. While advancements are being made to target particular driver mutations in AML, there is less focus on how to tackle the drug resistance of quiescent LSCs. This review summarises the current knowledge on the biochemical characteristics of quiescent HSCs and LSCs, the intracellular signaling pathways and the niche-driven mechanisms that control quiescence and the key differences between HSC- and LSC-quiescence that may be exploited for therapy.

Keywords:  Acute myeloid leukemia (AML); Bone marrow microenvironment; Cytokines, Chemokines; Drug resistance; Hematopoietic niche; Hematopoietic stem cells (HSC); Leukemic stem cells (LSC); Quiescence; Relapse

DOI:  https://doi.org/10.1016/j.blre.2021.100850
Front Oncol. 2021 ;11 673506

The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies.

Carolina Simioni, Ilaria Conti, Gabriele Varano, Cinzia Brenna, Eva Costanzi, Luca M Neri.

  The microenvironment that surrounds a tumor, in addition to the tumor itself, plays an important role in the onset of resistance to molecularly targeted therapies. Cancer cells and their microenvironment interact closely between them by means of a molecular communication that mutually influences their biological characteristics and behavior. Leukemia cells regulate the recruitment, activation and program of the cells of the surrounding microenvironment, including those of the immune system. Studies on the interactions between the bone marrow (BM) microenvironment and Acute Lymphoblastic Leukemia (ALL) cells have opened a scenario of potential therapeutic targets which include cytokines and their receptors, signal transduction networks, and hypoxia-related proteins. Hypoxia also enhances the formation of new blood vessels, and several studies show how angiogenesis could have a key role in the pathogenesis of ALL. Knowledge of the molecular mechanisms underlying tumor-microenvironment communication and angiogenesis could contribute to the early diagnosis of leukemia and to personalized molecular therapies. This article is part of a Special Issue entitled: Innovative Multi-Disciplinary Approaches for Precision Studies in Leukemia edited by Sandra Marmiroli (University of Modena and Reggio Emilia, Modena, Italy) and Xu Huang (University of Glasgow, Glasgow, United Kingdom).

Keywords:  ALL; HIF; angiogenesis; bone marrow; hypoxia; microenvironment; therapies

DOI:  https://doi.org/10.3389/fonc.2021.673506
Clin Exp Pharmacol Physiol. 2021 May 28.

Mechanisms of Cancer Stem Cell Senescence: Current Understanding and Future Perspectives.

Da-Yong Zhang, Michael J Monteiro, Jun-Ping Liu, Wen-Yi Gu.

  Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non-proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell towards stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.

Keywords:  Cancer stem cells; Cancer stemness; Cellular senescence; Molecular mechanism; Senolytic therapy; Tumor heterogeneity; Tumor therapy

DOI:  https://doi.org/10.1111/1440-1681.13528
J Food Biochem. 2021 May 24. e13772

Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics.

Kanchan Gairola, Shriya Gururani, Ananya Bahuguna, Vaishali Garia, Rohit Pujari, Shiv K Dubey.

  Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal. PRACTICAL APPLICATIONS: Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.

Keywords:  cancer stem cells; chemoprevention; natural products; signaling pathways

DOI:  https://doi.org/10.1111/jfbc.13772