bims-almceb 2022-05-08 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022‒05‒08
ten papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul

The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells.
Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.
Quiescence regulation by normal hematopoietic stem cells and leukemia stem cells.
TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes.
Drug resistance in cancer therapy: the Pandora's Box of cancer stem cells.
Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape.
Melatonin: A mitochondrial resident with a diverse skill set.
Age-Adjusted Schedules of Venetoclax and Hypomethylating Agents to Treat Extremely Elderly Patients with Acute Myeloid Leukemia.
LAG3-PD-1 Combo Overcome the Disadvantage of Drug Resistance.
The Effects of PI3K/Akt/mTOR Signaling Pathway Inhibitors on the Expression of Immune Checkpoint Ligands in Acute Myeloid Leukemia Cell Line.

Front Oncol. 2022 ;12 855570

The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells.

Xiangyu Ma, Mengjie Zhao, Zhuo-Xun Wu, Jingfang Yao, Lei Zhang, Jinhong Wang, Zhenbo Hu, Liuya Wei, Zhe-Sheng Chen.

  Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by reduced differentiation of myeloid cells and uncontrolled cell proliferation. AML is prone to drug resistance and has a high recurrence rate during treatment with cytarabine-based chemotherapy. Our study aims to explore the cell differentiation effect of a potent histone deacetylase inhibitor (HDACi), I13, and its possible mechanism on AML cell lines (Kasumi-1, KG-1, MOLM-13 and NB4). It has been shown that I13 can significantly inhibit proliferation and colony formation of these AML cells by inducing cell differentiation coupled with cell-cycle exit at G0/G1. Mechanically, I13 presented the property of HDAC inhibition, as assessed by the acetylation of histone H3, which led to the differentiation of Kasumi-1 cells. In addition, the HDAC inhibition of I13 likely dictated the activation of the antigen processing and presentation pathway, which maybe has the potential to promote immune cells to recognize leukemic cells and respond directly against leukemic cells. These results indicated that I13 could induce differentiation of M3 and M5 subtypes of AML cells, M2 subtype AML cells with t(8;21) translocation and leukemic stem-like cells. Therefore, I13 could be an alternative compound which is able to overcome differentiation blocks in AML.

Keywords:  HDAC inhibitor; acute myeloid leukemia; antigen processing and presentation; blockage of differentiation; differentiation therapy

DOI:  https://doi.org/10.3389/fonc.2022.855570
EMBO Mol Med. 2022 May 06. e15203

Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.

Joan So, Alexander C Lewis, Lorey K Smith, Kym Stanley, Rheana Franich, David Yoannidis, Lizzy Pijpers, Pilar Dominguez, Simon J Hogg, Stephin J Vervoort, Fiona C Brown, Ricky W Johnstone, Gabrielle McDonald, Danielle B Ulanet, Josh Murtie, Emily Gruber, Lev M Kats.

  The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

Keywords:  DHODH; acute myeloid leukemia; leukemic stem cells; protein translation

DOI:  https://doi.org/10.15252/emmm.202115203
FEBS J. 2022 May 05.

Quiescence regulation by normal hematopoietic stem cells and leukemia stem cells.

Kristbjorn Orri Gudmundsson, Yang Du.

  The hematopoietic system is maintained by rare hematopoietic stem cells (HSCs), which are quiescent most of the time and only divide occasionally to self-renew and/or to undergo commitment to clonal expansion via the generation of highly proliferative progenitor cells. The latter is responsible for the generation of all mature cells of the system through subsequent lineage commitment and terminal differentiation. Cells with similar properties also exist in leukemias and are known as leukemia stem cells (LSCs). Quiescence provides essential protection for both HSC and LSC from cytotoxic stress and DNA damage and, in the case of LSCs, likely causes therapy resistance and disease relapse in leukemia patients. Specific inhibition of LSC quiescence has been considered a promising strategy for eliminating LSCs and curing leukemias. Although the understanding of mechanisms responsible for quiescence maintenance in these cells remains limited, particularly for LSCs, recent studies have suggested potential differences in their dependency on certain pathways and their levels of stress and DNA damage caused by increased cycling. Such differences likely stem from oncogenic mutations in LSCs and could be specifically exploited for the elimination of LSCs while sparing normal HSCs in the future.

Keywords:  Hematopoietic stem cells; acute myeloid leukemia; cell cycle; leukemia stem cells; quiescence

DOI:  https://doi.org/10.1111/febs.16472
Front Oncol. 2022 ;12 879471

TIM-3 Expression Level on AML Blasts Correlates With Presence of Core Binding Factor Translocations Rather Than Clinical Outcomes.

Jian Hong, Leiming Xia, Zhenqi Huang, Xiaodong Yuan, Xinglin Liang, Jifei Dai, Zhonghui Wu, Li Liang, Min Ruan, Zhangbiao Long, Xin Cheng, Xiaowen Chen, Jing Ni, Jian Ge, Qingsheng Li, Qingshu Zeng, Ruixiang Xia, Yi Wang, Mingzhen Yang.

  Background: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) expresses on leukemic stem and progenitor populations of non-M3 acute myeloid leukemia (AML) as well as T lymphocytes. TIM-3 is thought to be involved in the self-renewal of leukemic stem cells and the immune escape of AML cells, however its correlation with AML prognosis is still controversial and worthy of further investigation.Methods: we simultaneously assessed TIM-3 expression levels of leukemic blasts and T lymphocytes in the bone marrow of de novo AML patients using flow cytometry. The correlations of TIM-3 expression between leukemic blasts and T lymphocytes and the correlations of TIM-3 expression with various patient parameters were analyzed. In addition, the Cancer Genome Atlas (TCGA) data of AML patients were acquired and analyzed to verify the results.
Results: TIM-3 expression of CD34+ leukemic blasts (R2 = 0.95, p<0.0001) and CD34+CD38- leukemic stem cells (R2 = 0.75, p<0.0001) were significantly and positively correlated with that of the whole population of leukemic blasts. In addition, TIM-3 expression level of leukemic blasts correlated significantly and positively with that of CD8+ (R2 = 0.44, p<0.0001) and CD4+ (R2 = 0.16, p=0.0181) lymphocytes, and higher TIM-3 expression of leukemic blasts was significantly associated with a greater proportion of peripheral CD8+ T lymphocytes (R2 = 0.24, p=0.0092), indicating that TIM-3 on leukemic blasts might alter adaptive immunity of AML patients. Regarding clinical data, the presence of core binding factor (CBF) translocations was significantly correlated with higher TIM-3 expression of leukemic blasts (CBF versus non-CBF, median 22.78% versus 1.28%, p=0.0012), while TIM-3 expression levels of leukemic blasts were not significantly associated with the remission status after induction chemotherapy (p=0.9799), overall survival (p=0.4201) or event-free survival (p=0.9873). Similar to our results, TCGA data showed that patients with CBF translocations had significantly higher mRNA expression level of HAVCR2 (the gene encoding TIM-3) (median, 9.81 versus 8.69, p<0.0001), and as all patients in the cohort were divided into two groups based on the median HAVCR2 expression level, 5-year overall survivals were not significantly different (low versus high, 24.95% versus 24.54%, p=0.6660).
Conclusion: TIM-3 expression level on AML blasts correlates with presence of CBF translocations rather than clinical outcomes.

Keywords:  TIM-3; acute myeloid leukemia; core binding factor translocation; flow cytometry; prognosis

DOI:  https://doi.org/10.3389/fonc.2022.879471
Stem Cell Res Ther. 2022 May 03. 13(1): 181

Drug resistance in cancer therapy: the Pandora's Box of cancer stem cells.

Hamed Rezayatmand, Mahboobeh Razmkhah, Iman Razeghian-Jahromi.

  Drug resistance is the main culprit of failure in cancer therapy that may lead to cancer relapse. This resistance mostly originates from rare, but impactful presence of cancer stem cells (CSCs). Ability to self-renewal and differentiation into heterogeneous cancer cells, and harboring morphologically and phenotypically distinct cells are prominent features of CSCs. Also, CSCs substantially contribute to metastatic dissemination. They possess several mechanisms that help them to survive even after exposure to chemotherapy drugs. Although chemotherapy is able to destroy the bulk of tumor cells, CSCs are left almost intact, and make tumor entity resistant to treatment. Eradication of a tumor mass needs complete removal of tumor cells as well as CSCs. Therefore, it is important to elucidate key features underlying drug resistance raised by CSCs in order to apply effective treatment strategies. However, the challenging point that threatens safety and specificity of chemotherapy is the common characteristics between CSCs and normal peers such as signaling pathways and markers. In the present study, we tried to present a comprehensive appraisal on CSCs, mechanisms of their drug resistance, and recent therapeutic methods targeting this type of noxious cells.

Keywords:  Cancer stem cell; Chemotherapy resistance; Drug resistance; Mechanism; Treatment resistance

DOI:  https://doi.org/10.1186/s13287-022-02856-6
Curr Res Immunol. 2021 ;2 132-141

Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape.

Tania Sarkar, Subhanki Dhar, Gaurisankar Sa.

  Tumor mass and its microenvironment alter host immune system in various ways to promote tumor growth. One of the modifications is evasion of immune surveillance by augmenting the number of Tregs in tumor vicinity. Elevated levels of Tregs are seen in peripheral circulation and tumor tissue of cancer patients. Cancer cells release several chemokines to attract Tregs in tumor-site. Infiltration of Tregs has clinical significance because being immunosuppressive infiltrating Tregs suppress other immune cells making the tumor microenvironment favorable for tumor growth. On the other hand, infiltrating Tregs show metabolic alteration in tumor microenvironment which allows their selective survival over the others. Persistence of Tregs in the tumor microenvironment and subsequent immunosuppression makes Tregs a potential therapeutic obstacle and the reason behind the failure of immunotherapy. In this review, we emphasize the recent development in the metabolic adaptation of tumor-infiltrating Tregs and the therapeutic approaches to boost immunity against cancer.

Keywords:  Anti-Tumor immunity; CCL/CXCL, Chemokine ligand; CCR/CXCR, Chemokine receptor; FOXP3, Forkhead box P3; IL, Interleukin; Immune-suppression; Metabolism; NK cell, Natural killer cell; T-regulatory cell; TGFβ, Transforming growth factor-beta; TME, Tumor microenvironment; Treg, T-regulatory cell; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.crimmu.2021.08.002
Life Sci. 2022 May 03. pii: S0024-3205(22)00312-5. [Epub ahead of print] 120612

Melatonin: A mitochondrial resident with a diverse skill set.

Russel J Reiter, Ramaswamy Sharma, Sergio Rosales-Corral, Debora Aparecida Pires de Campos Zuccari, Luiz Gustavo de Almeida Chuffa.

  Melatonin is an ancient molecule that originated in bacteria. When these prokaryotes were phagocytized by early eukaryotes, they eventually developed into mitochondria and chloroplasts. These new organelles retained the melatonin synthetic capacity of their forerunners such that all present-day animal and plant cells may produce melatonin in their mitochondria and chloroplasts. Melatonin concentrations are higher in mitochondria than in other subcellular compartments. Isolated mouse oocyte mitochondria form melatonin when they are incubated with serotonin, a necessary precursor. Oocyte mitochondria subsequently give rise to these organelles in all adult vertebrate cells where they continue to synthesize melatonin. The enzymes that convert serotonin to melatonin, i.e., arylalkylamine-N-acetyltransferase (AANAT) and acetylserotonin-O-methyltransferase, have been identified in brain mitochondria which, when incubated with serotonin, also form melatonin. Melatonin is a potent antioxidant and anti-cancer agent and is optimally positioned in mitochondria to aid in the maintenance of oxidative homeostasis and to reduce cancer cell transformation. Melatonin stimulates the transfer of mitochondria from healthy cells to damaged cells via tunneling nanotubes. Melatonin also regulates the major NAD+-dependent deacetylase, sirtuin 3, in the mitochondria. Disruptions of mitochondrial melatonin synthesis may contribute to a number of mitochondria-related diseases, as discussed in this review.

Keywords:  Acetyl coenzyme a; Pyruvate metabolism; SIRT3; Tunneling nanotubes; cancer; sepsis

DOI:  https://doi.org/10.1016/j.lfs.2022.120612
Case Rep Hematol. 2022 ;2022 2802680

Age-Adjusted Schedules of Venetoclax and Hypomethylating Agents to Treat Extremely Elderly Patients with Acute Myeloid Leukemia.

Aaron M Lee, Aaron M Goodman, James K Mangan.

Acute myeloid leukemia (AML) is associated with particularly poor outcomes in the elderly population, in whom the disease is most prevalent. BCL-2 has been identified as an antiapoptotic protein and promotes survival of leukemia stem cells. Recently, the United States FDA has approved venetoclax, a selective oral BCL-2 inhibitor, for use in conjunction with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine as a first-line treatment option for those AML patients ineligible for standard induction chemotherapy. However, there are nuances and challenges when using this regimen in the extremely elderly AML patients. Given the widespread adoption of this regimen and increasing prevalence of patients who are well into their 80 s, it is important to evaluate and understand how to safely use this regimen in this so-called "extremely elderly" population. We present here 3 case studies involving AML patients >85 years of age who were treated with venetoclax plus HMA and provide clinical knowledge on how this population should be appropriately managed.

DOI: https://doi.org/10.1155/2022/2802680
Front Oncol. 2022 ;12 831407

LAG3-PD-1 Combo Overcome the Disadvantage of Drug Resistance.

Yiming Wei, Zhaoming Li.

  Although PD-1 blockade therapy has been promising in cancer treatment, only 4% (pancreatic cancer) to 70% (melanoma) of patients have a positive response to this blockade therapy, which is one of its important disadvantages. Therefore, it is important to seek out new targets for cancer immunotherapy to improve the overall response rate in patients. Lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor, is mainly expressed in activated immune cells. LAG-3 maintains the body's immune homeostasis under physiological conditions while mediating tumour immune escape. Several preclinical and clinical examinations have shown that LAG-3 blockade effectively alleviates the patient's tolerance to PD-1 immune checkpoint inhibitors. Moreover, the combination of LAG-3 and PD-1 blockade has good clinical efficacy in cancers. Hence, synchronous LAG-3 and PD-1 inhibition may be a potential new strategy for tumour immunotherapy.

Keywords:  Lymphocyte Activation Gene-3 (LAG-3); Programmed Cell Death 1 (PD-1); drug resistance; immune checkpoint; immunotherapy

DOI:  https://doi.org/10.3389/fonc.2022.831407
Iran J Allergy Asthma Immunol. 2022 Apr 11. 21(2): 178-188

The Effects of PI3K/Akt/mTOR Signaling Pathway Inhibitors on the Expression of Immune Checkpoint Ligands in Acute Myeloid Leukemia Cell Line.

Saeid Taghiloo, Saeid Norozi, Hossein Asgarian-Omran.

  Up-regulation of immune checkpoint ligands is considered as one of the most important immune escape mechanisms in acute myeloid leukemia (AML). Herein, we investigate a relationship between the inhibition of PI3K/Akt/mTOR signaling pathways and the regulation of immune checkpoint ligands in AML cells. The HL-60 cell line was treated with idelalisib as PI3K inhibitor, MK-2206 as Akt inhibitor, and everolimus as mTOR inhibitor either in a single or combined format. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. The relative expression of PD-L1, galectin-9, and CD155 was determined by real-time PCR. Our findings demonstrated decreased proliferation and increased apoptosis of HL-60 cells after treatment with idelalisib, MK-2206, and everolimus. As expected, the combined treatment showed a more inhibiting effect than the single treatment. Interestingly, our results elucidated that the expression of PD-L1 and Gal-9 but not MK-2206 decreased after treatment with idelalisib and everolimus. Regarding CD155, the expression of this molecule was downregulated after treatment with everolimus, but not idelalisib and MK-2206. However, combined treatment of HL-60 cells with two or three inhibitors decreased the expression levels of PD-L1, Gal-9, and CD155 checkpoint ligands. We showed that PI3K/Akt/mTOR pathway inhibitors not only serve as cytotoxic drugs but also regulate the expression of immune checkpoint ligands and interfere with the immune evasion mechanisms of AML leukemic cells. Combinational treatment approaches to block these pathways might be a promising and novel therapeutic strategy for AML patients via interfering in immune escape mechanisms.

Keywords:  Acute myeloid leukemia; Everolimus; Idelalisib; Immune evasion; MK 2206

DOI:  https://doi.org/10.18502/ijaai.v21i2.9225