bims-almceb 2022-02-27 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–02–27
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation.
Over-Reduced State of Mitochondria as a Trigger of "β-Oxidation Shuttle" in Cancer Cells.
Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial-Hybrid-Mesenchymal Spectrum in Cancer.
Editorial: New Insights into the Complexity of Tumor Immunology in B-cell Malignancies: Tumor Immunology and Immunotherapy.
Identification, Culture and Targeting of Cancer Stem Cells.
Oncogenes and the Origins of Leukemias.
Pharmacotherapeutic management of T-cell acute lymphoblastic leukemia in adults: an update of the literature.
Autophagy in acute myeloid leukemia: a paradoxical role in chemoresistance.
The new mitochondrial uncoupler BAM15 induces ROS production for treatment of acute myeloid leukemia.

Stem Cell Rev Rep. 2022 Feb 21.

Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation.

Haoyue Liang, Shuxu Dong, Weichao Fu, Sen Zhang, Wenying Yu, Fang Dong, Baolin He, Jinhong Wang, Yingdai Gao, Yuan Zhou, Yongxin Ru.

   BACKGROUND: The heterogeneity of mitochondrial function is an important feature of hematopoietic cell lineage differentiation, but its stage wise contribution is not adequately studied. To establish a model to compare the lineage differentiation of hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and differentiated blood cells, the mitochondrial mass (MM), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy level were analyzed.
RESULTS AND DISCUSSION: HSCs had lower mitochondrial metabolic activity than committed progenitor populations, indicated by lower MM, MMP, and ROS and higher mitophagy. HPC1s shared more stem cell characteristics than HPC2s and committed progenitor populations in terms of mitochondrial number and function. The mitochondrial metabolism of mature blood cells had greater heterogeneity than hematopoietic stem and progenitor cells, with granulocytes being similar to monocytes. Moreover, HSCs exhibited heterogeneity in the selection of mitophagy-related PINK1/PARK2, BNIP3/NIX, and FUNDC1 pathways. Myeloid differentiation had greater morphological and functional heterogeneity of hematopoietic cells than lymphoid differentiation. Additionally, leukemia stem cells had higher aerobic metabolism and better stem cell function through elevated mitophagy than normal hematopoietic cells. ROS and MMP levels in differentiated leukemia cells were higher, but the level of mitophagy was lower than in differentiated hematopoietic cells.
CONCLUSION: This study provides a complete set of methods and basic reference values for the systematic study of the mitochondrial metabolic function of different types of hematopoietic cells under physiological and pathological conditions. The findings contribute to the future research of tumor and aging based on mitochondrial metabolism.

Keywords:  Hematopoietic cell; Lineage differentiation; Metabolic map; Mitochondrial function; Mitophagy

DOI:  https://doi.org/10.1007/s12015-022-10354-8
Cancers (Basel). 2022 Feb 10. pii: 871. [Epub ahead of print]14(4):

Over-Reduced State of Mitochondria as a Trigger of "β-Oxidation Shuttle" in Cancer Cells.

Zhivko Zhelev, Akira Sumiyoshi, Ichio Aoki, Dessislava Lazarova, Tatyana Vlaykova, Tatsuya Higashi, Rumiana Bakalova.

  A considerable amount of data have accumulated in the last decade on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. As a result, mFAO was found to coexist with abnormally activated fatty acid synthesis (FAS) and the mevalonate pathway. Recent studies have demonstrated that overactivated mitochondrial β-oxidation may aggravate the impaired mitochondrial redox state and vice versa. Furthermore, the impaired redox state of cancerous mitochondria can ensure the continuous operation of β-oxidation by disconnecting it from the Krebs cycle and connecting it to the citrate-malate shuttle. This could create a new metabolic state/pathway in cancer cells, which we have called the "β-oxidation-citrate-malate shuttle", or "β-oxidation shuttle" for short, which forces them to proliferate. The calculation of the phosphate/oxygen ratio indicates that it is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathways. The "β-oxidation shuttle" is an unconventional mFAO, a separate metabolic pathway that has not yet been explored as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and, ultimately, a source of proliferation. The role of the "β-oxidation shuttle" and its contribution to redox-altered cancer metabolism provides a new direction for the development of future anticancer strategies. This may represent the metabolic "secret" of cancer underlying hypoxia and genomic instability.

Keywords:  cancer; metabolism; mitochondrial fatty acid oxidation; β-oxidation shuttle

DOI:  https://doi.org/10.3390/cancers14040871
Biomolecules. 2022 Feb 12. pii: 297. [Epub ahead of print]12(2):

Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial-Hybrid-Mesenchymal Spectrum in Cancer.

Srinath Muralidharan, Sarthak Sahoo, Aryamaan Saha, Sanjay Chandran, Sauma Suvra Majumdar, Susmita Mandal, Herbert Levine, Mohit Kumar Jolly.

  Cancer metastasis is the leading cause of cancer-related mortality and the process of the epithelial-to-mesenchymal transition (EMT) is crucial for cancer metastasis. Both partial and complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among the oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways and their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show the diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. The analysis of single-cell data for EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Further, assessing the association of EMT and metabolic activity with patient survival shows that a higher extent of EMT and glycolysis predicts a worse prognosis in many cancers. Together, our results reveal the underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.

Keywords:  AMPK; HIF1α; cancer metabolism; epithelial–mesenchymal transition; fatty acid metabolism; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom12020297
Front Oncol. 2022 ;12 853620

Editorial: New Insights into the Complexity of Tumor Immunology in B-cell Malignancies: Tumor Immunology and Immunotherapy.

Martina Seiffert, Etienne Moussay, Jérôme Paggetti.



Keywords:  anti-tumor immunity; chronic lymphocytic leukemia (CLL); immunotherapy; leukemia; lymphoma; stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.853620
Life (Basel). 2022 Jan 27. pii: 184. [Epub ahead of print]12(2):

Identification, Culture and Targeting of Cancer Stem Cells.

Alejandro Herreros-Pomares.

  Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required.

Keywords:  CSC culture; CSC makers; Hippo pathway; Wnt pathway; cancer stem cells; cell culture; hedgehog pathway; notch pathway

DOI:  https://doi.org/10.3390/life12020184
Int J Mol Sci. 2022 Feb 18. pii: 2293. [Epub ahead of print]23(4):

Oncogenes and the Origins of Leukemias.

Geoffrey Brown.

  Self-maintaining hematopoietic stem cells are a cell population that is primarily 'at risk' to malignant transformation, and the cell-of-origin for some leukemias. Tissue-specific stem cells replenish the different types of functional cells within a particular tissue to meet the demands of an organism. For hematopoietic stem cells, this flexibility is important to satisfy the changing requirements for a certain type of immune cell, when needed. From studies of the natural history of childhood acute lymphoblastic leukemia, an initial oncogenic and prenatal insult gives rise to a preleukemic clone. At least a second genomic insult is needed that gives rise to a leukemia stem cell: this cell generates a hierarchy of leukemia cells. For some leukemias, there is evidence to support the concept that one of the genomic insults leads to dysregulation of the tissue homeostatic role of hematopoietic stem cells so that the hierarchy of differentiating leukemia cells belongs to just one cell lineage. Restricting the expression of particular oncogenes in transgenic mice to hematopoietic stem and progenitor cells led to different human-like lineage-restricted leukemias. Lineage restriction is seen for human leukemias by virtue of their sub-grouping with regard to a phenotypic relationship to just one cell lineage.

Keywords:  leukemia; lineage fate; oncogenes; stem cells

DOI:  https://doi.org/10.3390/ijms23042293
Expert Opin Pharmacother. 2022 Feb 22. 1-11

Pharmacotherapeutic management of T-cell acute lymphoblastic leukemia in adults: an update of the literature.

Alexander Grunenberg, Elisa Sala, Silke Kapp-Schwoerer, Andreas Viardot.

   INTRODUCTION: T-cell acute lymphoblastic leukemia (T-ALL) is a rare but potentially life-threatening heterogeneous hematologic malignancy that requires prompt diagnosis and treatment by hematologists. So far, therapeutic advances have been achieved in the management of this disease mainly by adopting pediatric-like regimens, and cure rates are significantly worse than in childhood. In T-ALL, less than 70% of adults achieve long-term survival. The prognosis after relapse is still very poor. Hence, there is urgent need to improve therapy of T-ALL by testing new compounds and combinations for the treatment of this disease.
AREAS COVERED: This review provides a comprehensive update on the most recent treatment approaches in adults with de novo and relapsed/refractory adult T-ALL.
EXPERT OPINION: Intensifying chemotherapy may reduce the incidence of recurrent disease in adult patients, but it has not come without a cost. Novel agents with selective T-ALL activity (e.g. nelarabine) may improve survival in some patient subsets. Due to modern genomic and transcriptomic techniques, various novel potential targets might change the treatment landscape in the next few years and will, hopefully alongside with cellular therapies, augment the therapeutic armamentarium in the near future.

Keywords:  Acute lymphoblastic leukemia; allogeneic stem cell transplantation; measurable residual disease; nelarabine

DOI:  https://doi.org/10.1080/14656566.2022.2033725
Clin Transl Oncol. 2022 Feb 26.

Autophagy in acute myeloid leukemia: a paradoxical role in chemoresistance.

Aafreen Khan, Vivek Kumar Singh, Deepshi Thakral, Ritu Gupta.

  Autophagy is a lysosomal degradation pathway that is constitutively active in almost every cell of our body at basal level. This self-eating process primarily serves to remove superfluous constituents of the cells and recycle the degraded products. Autophagy plays an essential role in cell homeostasis and can be enhanced in response to stressful conditions. Impairment in the regulation of the autophagic pathway is implicated in pathological conditions such as neurodegeneration, cardiac disorders, and cancer. However, the role of autophagy in cancer initiation and development is controversial and context-dependent. Evidence from various studies has shown that autophagy serves dual purpose and may assist in cancer progression or suppression. In the early stages of cancer initiation, autophagy acts as a quality control mechanism and prevents cancer development. When cancer is established and progresses to a later stage, autophagy helps in the survival of these cells through adaptation to stresses, including exposure to anti-cancer drugs. In this review, we highlight various studies on autophagic pathways and describe the role of autophagy in cancer, specifically acute myeloid leukemia (AML). We also discuss the prognostic significance of autophagy genes involved in AML leukemogenesis and implications in conferring resistance to chemotherapy.

Keywords:  Acute myeloid leukemia; Autophagy; Autophagy-related protein (ATG); Drug resistance

DOI:  https://doi.org/10.1007/s12094-022-02804-z
Biochem Pharmacol. 2022 Feb 19. pii: S0006-2952(22)00042-9. [Epub ahead of print] 114948

The new mitochondrial uncoupler BAM15 induces ROS production for treatment of acute myeloid leukemia.

Zhen Xing Gao, Ze Long Cui, Min Ran Zhou, Yue Fu, Fen Liu, Lu Zhang, Sai Ma, Chun Yan Chen.

  Acute myeloid leukemia (AML) is a malignant proliferative disease of myeloid hematopoietic origin and cannot be treated appropriately at present. This is due to the fact that leukemia cells are not sensitive to some of the traditional chemotherapy drugs. Or some chemotherapeutic drugs are too toxic to normal cells, affecting their wide clinical application. In this study, we identified BAM15 as a novel mitochondrial uncoupling agent by screening a library of small molecule compounds that inhibit AML cell activity. BAM15 significantly inhibited proliferation and promoted apoptosis in AML cells while at the same time being less cytotoxic to normal cells. The mechanism may be related to the disturbance of the ROS production balance. In vivo investigations revealed that BAM15 effectively suppressed AML progression and prolonged the survival time of mice. In addition, we found that BAM15 can be used in combination with cytarabine to enhance its anti-cancer activity and inhibit the activity of primary cells in AML. Therefore, we identified BAM15 as a potential drug candidate for the treatment of AML.

Keywords:  BAM15; ROS; apoptosis; leukemia; primary cells; proliferation

DOI:  https://doi.org/10.1016/j.bcp.2022.114948