Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

Bhingarkar, Aboli; Vangapandu, Hima V.; Rathod, Sanjay; Hoshitsuki, Keito; Fernandez, Christian A.

doi:10.3389/fonc.2021.694526

Cited by 5 publications

(4 citation statements)

References 245 publications

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“…In this research, we also showed a high expression of gamma-cystathionase in K562 cells ( Figure 2 , Figure 3 and Figure 7 A,B). These results confirm the existing literature data, which shows the presence of CTH in chronic myeloid leukemia cells [ 45 , 46 ]. Glode et al [ 45 ] reported that CTH was detected in K562 (CML) and HL-60 (AML) cell lines; these cell lines were not capable of sustained logarithmic growth in the absence of L-cysteine.…”

Section: Discussionsupporting

confidence: 93%

Sulfurtransferases and Cystathionine Beta-Synthase Expression in Different Human Leukemia Cell Lines

et al. 2022

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The studies concerned the expression of sulfurtransferases and cystathionine beta-synthase in six human leukemia cell lines: B cell acute lymphoblastic leukemia-B-ALL (REH cells), T cell acute lymphoblastic leukemia-T-ALL (DND-41 and MOLT-4 cells), acute myeloid leukemia—AML (MV4-11 and MOLM-14 cells), and chronic myeloid leukemia—CML (K562 cells). Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis were performed to determine the expression of thiosulfate sulfurtransferase, 3-mercaptopyruvate sulfurtransferase, gamma-cystathionase, and cystathionine beta-synthase on the mRNA and protein level. Interestingly, we found significant differences in the mRNA and protein levels of sulfurtransferases and cystathionine beta-synthase in the studied leukemia cells. The obtained results may contribute to elucidating the significance of the differences between the studied cells in the field of sulfur compound metabolism and finding new promising ways to inhibit the proliferation of various types of leukemic cells by modulating the activity of sulfurtransferases, cystathionine beta-synthase, and, consequently, the change of intracellular level of sulfane sulfur as well as H2S and reactive oxygen species production.

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Section: Discussionsupporting

confidence: 93%

Sulfurtransferases and Cystathionine Beta-Synthase Expression in Different Human Leukemia Cell Lines

et al. 2022

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“…Interestingly, in CML-derived Hap1 cells, altered glutamine usage was not readily observed from loss of SLC25A51 (Supplementary Fig. S3A), underscoring metabolic differences between different leukemia lines (37).…”

Section: Discussionmentioning

confidence: 94%

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

Busquets

Impedovo

et al. 2022

Preprint

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SLC25A51 imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining oxidative metabolism in human mitochondria. We observed that higher expression of SLC25A51 correlated with poorer survival in Acute Myeloid Leukemia (AML) patient data. Given AML's dependency on oxidative cell metabolism, we sought to determine the role SLC25A51 may serve in this disease. We found that depleting SLC25A51 in AML cells led to increased apoptosis, as well as prolonged survival in a xenograft model. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and promoted glutamine utilization for reductive carboxylation to support aspartate production. Consequently, SLC25A51 loss sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the work highlights connections between SLC25A51 and oxidative mitochondrial flux in AML. We identified a rationale for targeting SLC25A51 in myeloid cancers with potential for a therapeutic window, especially when coupled with glutaminase inhibition.

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“…Furthermore, amino acid synthesis pathways are also reprogrammed to supply nucleotides for the cancer metabolism. Recent reports have supported the role of one-carbon metabolism in cancel cell survival, growth, and proliferation (Bhingarkar et al 2021 ; Krall et al 2016 ; Lieu et al 2020 ; Sahu et al 2016 ). Since CTPsyn is involved in the de novo pyrimidine synthesis pathway, Fig.…”

Section: Ctpsyn Activity and Its Filamentation From A Disease Perspec...mentioning

confidence: 88%

CTP synthase: the hissing of the cellular serpent

Thangadurai

Bajgiran

Manickam

et al. 2022

Histochem Cell Biol

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CTP biosynthesis is carried out by two pathways: salvage and de novo. CTPsyn catalyzes the latter. The study of CTPsyn activity in mammalian cells began in the 1970s, and various fascinating discoveries were made regarding the role of CTPsyn in cancer and development. However, its ability to fit into a cellular serpent-like structure, termed ‘cytoophidia,’ was only discovered a decade ago by three independent groups of scientists. Although the self-assembly of CTPsyn into a filamentous structure is evolutionarily conserved, the enzyme activity upon this self-assembly varies in different species. CTPsyn is required for cellular development and homeostasis. Changes in the expression of CTPsyn cause developmental changes in Drosophila melanogaster . A high level of CTPsyn activity and formation of cytoophidia are often observed in rapidly proliferating cells such as in stem and cancer cells. Meanwhile, the deficiency of CTPsyn causes severe immunodeficiency leading to immunocompromised diseases caused by bacteria, viruses, and parasites, making CTPsyn an attractive therapeutic target. Here, we provide an overview of the role of CTPsyn in cellular and disease perspectives along with its potential as a drug target.

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Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

Cited by 5 publications

References 245 publications

Sulfurtransferases and Cystathionine Beta-Synthase Expression in Different Human Leukemia Cell Lines

Sulfurtransferases and Cystathionine Beta-Synthase Expression in Different Human Leukemia Cell Lines

SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

CTP synthase: the hissing of the cellular serpent

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