bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022–06–19
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. The Emerging Roles of Aldehyde Dehydrogenase in Acute Myeloid Leukemia and its Therapeutic Potential.
  2. Prognostic Impact and Phenotype of Residual Acute Myeloid Leukemia Stem Cells.
  3. PGC-1α participates in tumor chemoresistance by regulating glucose metabolism and mitochondrial function.
  4. New dawn for cancer cell death: emerging role of lipid metabolism.
  5. Childhood Acute B-Lineage Lymphoblastic Leukemia With CDKN2A/B Deletion Is a Distinct Entity With Adverse Genetic Features and Poor Clinical Outcomes.
  6. Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.
  7. Next-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy.
  8. The local microenvironment matters in preclinical basic and translational studies of cancer immunology and immunotherapy.
  9. Immune cell metabolism and metabolic reprogramming.
  1. Anticancer Agents Med Chem. 2022 Jun 10.
    The Emerging Roles of Aldehyde Dehydrogenase in Acute Myeloid Leukemia and its Therapeutic Potential.
    Atefe Rahmati, Sajad Goudarzi, Maryam Sheikhi, Payam Siyadat, Gordon A Ferns, Hossein Ayatollahi.
      Acute myeloid leukemia (AML) is a malignant disorder characterized by myeloid differentiation arrest and uncontrolled clonal expansion of abnormal myeloid progenitor cells. AML is the most common malignant bone marrow (BM) disease in adults and accounts for approximately 80% of adult leukemia cases. There has been little improvement in the treatment of patients with AML over the past decade. Cytogenetic and morphologic heterogeneity of AML and the difficulty in distinguishing leukemic stem cells (LSCs) from normal hematopoietic stem cells (HSCs) continue to be the major challenges in treating this malignancy. In recent years, intensive efforts have been made to explore novel potential markers for the efficient identification and characterization of leukemic stem cells. Aldehyde dehydrogenase (ALDH) is a potential target molecule that plays crucial roles in leukemic stem cell survival and multidrug resistance, mainly through its involvement in the detoxification of many endogenous and exogenous aldehydes. The selection and isolation of cancer stem cells based on high ALDH activity seem to be a useful approach in many human malignancies, especially leukemia. Moreover, it is worth mentioning that several previous studies have indicated that a high ALDH activity (classified as ALDHbr cells in flow cytometry) can act as an independent prognostic factor in several types of cancer. In the present review, we update and critically discuss the available data regarding the importance of ALDH activity in normal and leukemic stem cells and its potential diagnostic and therapeutic implications.
    Keywords:  Aldehyde dehydrogenase; acute myeloid leukemia; hematopoietic stem cell; leukemic stem cell; targeted therapy
    DOI:  https://doi.org/10.2174/1871520622666220610154043
  2. Clin Lab. 2022 Jun 01. 68(6):
    Prognostic Impact and Phenotype of Residual Acute Myeloid Leukemia Stem Cells.
    Samiha Jaddaoui, Hanaa Bencharef, Mouna Lamchahab, Asmaa Quessar, Bouchra Oukkache.
       BACKGROUND: Leukemia stem cells (LSCs) have been demonstrated to be more therapy-resistant than leukemic blast cells reflecting measurable residual disease (MRD). CD34+CD38- cell frequency is an independent factor for relapse prediction and could therefore be used in the future to improve MRD assessment in acute myeloid leukemia (AML). This protocol is designed to enable accurate and reproducible immunophenotypic detection of measurable residual stem cell disease necessary for proper therapeutic decision and report their prognostic value in AML patients.
    METHODS: Fifty-four Novo AML adult patients diagnosed in the onco-hematology service of the "20 August 1953" Hospital in Casablanca. We analyzed phenotype and frequency of CD45dim CD34+CD38- cells in bone marrow samples from patients with AML and non-myeloid malignancies using six-color flow cytometry and a simple one-tube essay.
    RESULTS: For evaluation of leukemic stem cells, our gate strategy was based on the selection of CD34+CD38 - stem cells and leukemia associated immunophenotype approach. Positivity of CD123 or/and aberrant expression of primitive markers CD117 and HLA DR on stem cells discriminate leukemia stem cells from normal hematopoietic stem cells. We reported a statistically significant difference between expressions of primitive markers (CD117 and HLA DR) on leukemic stem cells. In addition, the frequency of LSCs after complete remission in post-induction was persistent in 50% of AML patients.
    CONCLUSIONS: Overall, we show that CD34+CD38-CD123+ as a basic phenotype, with aberrant phenotype detection of HLA DR and CD117 markers on stem cells, contributes to detecting LSCs which indicates the poor prognosis.
    DOI:  https://doi.org/10.7754/Clin.Lab.2021.210821
  3. Mol Cell Biochem. 2022 Jun 17.
    PGC-1α participates in tumor chemoresistance by regulating glucose metabolism and mitochondrial function.
    Yanqing Li, Hu Hei, Songtao Zhang, Wenbo Gong, Yann Liu, Jianwu Qin.
      Chemotherapy resistance is the main reason for the failure of cancer treatment. The mechanism of drug resistance is complex and diverse. In recent years, the role of glucose metabolism and mitochondrial function in cancer resistance has gathered considerable interest. The increase in metabolic plasticity of cancer cells' mitochondria and adaptive changes to the mitochondrial function are some of the mechanisms through which cancer cells resist chemotherapy. As a key molecule regulating the mitochondrial function and glucose metabolism, PGC-1α plays an indispensable role in cancer progression. However, the role of PGC-1α in chemotherapy resistance remains controversial. Here, we discuss the role of PGC-1α in glucose metabolism and mitochondrial function and present a comprehensive overview of PGC-1α in chemotherapy resistance.
    Keywords:  Cancer; Chemoresistance; Metabolism; Mitochondrion; PGC-1α
    DOI:  https://doi.org/10.1007/s11010-022-04477-2
  4. Mol Metab. 2022 Jun 14. pii: S2212-8778(22)00098-9. [Epub ahead of print] 101529
    New dawn for cancer cell death: emerging role of lipid metabolism.
    Chanjuan Zhang, Neng Zhu, Hongfang Li, Yongzhen Gong, Jia Gu, Yaning Shi, Duanfang Liao, Wei Wang, Aiguo Dai, Li Qin.
       BACKGROUND: Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death.
    SCOPE OF REVIEW: We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient.
    MAJOR CONCLUSIONS: The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.
    Keywords:  Lipid metabolism; cancer; cell death; therapeutic strategy
    DOI:  https://doi.org/10.1016/j.molmet.2022.101529
  5. Front Oncol. 2022 ;12 878098
    Childhood Acute B-Lineage Lymphoblastic Leukemia With CDKN2A/B Deletion Is a Distinct Entity With Adverse Genetic Features and Poor Clinical Outcomes.
    Jing Feng, Ye Guo, Wenyu Yang, Yao Zou, Li Zhang, Yumei Chen, Yingchi Zhang, Xiaofan Zhu, Xiaojuan Chen.
      To further emphasize the clinical-genetic features and prognosis of CDKN2A/B deletions in childhood acute lymphoblastic leukemia (ALL), we retrospectively analyzed 819 consecutive B-ALL patients treated with the Chinese Children's Cancer Group ALL-2015 (CCCG-ALL-2015) protocol, and fluorescence in situ hybridization (FISH) analysis on CDKN2A/B deletion was available for 599 patients. The prevalence of CDKN2A/B gene deletions was 20.2% (121/599) of B-ALL. CDKN2A/B deletions were significantly associated with older age, higher leukocyte counts, a higher percentage of hepatosplenomegaly, and a higher frequency of BCR-ABL (p < 0.05). Those patients achieved similar minimal residual disease (MRD) clearance and complete remission compared to patients without CDKN2A/B deletion. The CDKN2A/B deletions were correlated with inferior outcomes, including a 3-year event-free survival (EFS) rate (69.8 ± 4.6 vs. 89.2 ± 1.6%, p = 0.000) and a 3-year overall survival (OS) rate (89.4% ± 2.9% vs. 94.7% ± 1.1%, p = 0.037). In multivariable analysis, CDKN2A/B deletion was still an independent prognostic factor for EFS in total cohorts (p < 0.05). We also detected a multiplicative interaction between CDKN2A/B deletions and TP53 deletion on dismal prognosis (p-interaction < 0.05). In conclusion, CDKN2A/B deletion is associated with distinct characteristics and serves as a poor prognostic factor in pediatric ALL, especially in TP53 deletion carriers.
    Keywords:  CDKN2A/B; TP53; fluorescence in situ hybridization; pediatric acute lymphoblastic leukemia; prognosis
    DOI:  https://doi.org/10.3389/fonc.2022.878098
  6. PLoS One. 2022 ;17(6): e0268963
    Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.
    Sharareh Siamakpour-Reihani, Felicia Cao, Jing Lyu, Yi Ren, Andrew B Nixon, Jichun Xie, Amy T Bush, Mark D Starr, James R Bain, Michael J Muehlbauer, Olga Ilkayeva, Virginia Byers Kraus, Janet L Huebner, Nelson J Chao, Anthony D Sung.
      Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.
    DOI:  https://doi.org/10.1371/journal.pone.0268963
  7. J Clin Invest. 2022 Jun 15. pii: e154945. [Epub ahead of print]132(12):
    Next-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy.
    Ahmed Halima, Winston Vuong, Timothy A Chan.
      Immunity is governed by fundamental genetic processes. These processes shape the nature of immune cells and set the rules that dictate the myriad complex cellular interactions that power immune systems. Everything from the generation of T cell receptors and antibodies, control of epitope presentation, and recognition of pathogens by the immunoediting of cancer cells is, in large part, made possible by core genetic mechanisms and the cellular machinery that they encode. In the last decade, next-generation sequencing has been used to dissect the complexities of cancer immunity with potent effect. Sequencing of exomes and genomes has begun to reveal how the immune system recognizes "foreign" entities and distinguishes self from non-self, especially in the setting of cancer. High-throughput analyses of transcriptomes have revealed deep insights into how the tumor microenvironment affects immunotherapy efficacy. In this Review, we discuss how high-throughput sequencing has added to our understanding of how immune systems interact with cancer cells and how cancer immunotherapies work.
    DOI:  https://doi.org/10.1172/JCI154945
  8. Cancer Cell. 2022 Jun 13. pii: S1535-6108(22)00229-X. [Epub ahead of print]
    The local microenvironment matters in preclinical basic and translational studies of cancer immunology and immunotherapy.
    William W Ho, Mikael J Pittet, Dai Fukumura, Rakesh K Jain.
      
    DOI:  https://doi.org/10.1016/j.ccell.2022.05.016
  9. Mol Biol Rep. 2022 Jun 13.
    Immune cell metabolism and metabolic reprogramming.
    Chenchen Hu, Yuxin Xuan, Xiyang Zhang, Yang Liu, Shuya Yang, Kun Yang.
      Energy metabolism maintains the activation of intracellular and intercellular signal transduction, and plays a crucial role in immune response. Under environmental stimulation, immune cells change from resting to activation and trigger metabolic reprogramming. The immune system cells exhibit different metabolic characteristics when performing functions. The study of immune metabolism provides new insights into the function of immune cells, including how they differentiate, migrate and exert immune responses. Studies of immune cell energy metabolism are beginning to shed light on the metabolic mechanism of disease progression and reveal new ways to target inflammatory diseases such as autoimmune diseases, chronic viral infections, and cancer. Here, we discussed the relationship between immune cells and metabolism, and proposed the possibility of targeted metabolic process for disease treatment.
    Keywords:  Immune cells; Immune metabolism; Metabolic reprogramming; Targeted therapy
    DOI:  https://doi.org/10.1007/s11033-022-07474-2
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