<i>In vivo</i>genetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia

Wei, Yiliang; Iyer, Subramania; Costa, S. V.; Yang, Zhaolin; Kramer, Melissa; Adelman, Emmalee R.; Klingbeil, Olaf; Demerdash, Osama E.; Polyanskaya, Sofya A.; Chang, Kenneth; Goodwin, Sara; Hodges, Emily; McCombie, W. Richard; Figueroa, María E.; Vakoc, Christopher R.

doi:10.1101/2020.12.22.424018

Cited by 5 publications

(5 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lee et al developed a new nanopore sequencing-based method to simultaneously detect CpG methylation and chromatin accessibility [86]. Also, several preprint papers report the use of nanopore sequencing to enhance the understanding of epigenetic heterogeneity and the underlying molecular mechanisms [87][88][89].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation

et al. 2021

View full text Add to dashboard Cite

Background Nanopore long-read sequencing technology greatly expands the capacity of long-range, single-molecule DNA-modification detection. A growing number of analytical tools have been developed to detect DNA methylation from nanopore sequencing reads. Here, we assess the performance of different methylation-calling tools to provide a systematic evaluation to guide researchers performing human epigenome-wide studies. Results We compare seven analytic tools for detecting DNA methylation from nanopore long-read sequencing data generated from human natural DNA at a whole-genome scale. We evaluate the per-read and per-site performance of CpG methylation prediction across different genomic contexts, CpG site coverage, and computational resources consumed by each tool. The seven tools exhibit different performances across the evaluation criteria. We show that the methylation prediction at regions with discordant DNA methylation patterns, intergenic regions, low CG density regions, and repetitive regions show room for improvement across all tools. Furthermore, we demonstrate that 5hmC levels at least partly contribute to the discrepancy between bisulfite and nanopore sequencing. Lastly, we provide an online DNA methylation database (https://nanome.jax.org) to display the DNA methylation levels detected by nanopore sequencing and bisulfite sequencing data across different genomic contexts. Conclusions Our study is the first systematic benchmark of computational methods for detection of mammalian whole-genome DNA modifications in nanopore sequencing. We provide a broad foundation for cross-platform standardization and an evaluation of analytical tools designed for genome-scale modified base detection using nanopore sequencing.

show abstract

Section: Discussionmentioning

confidence: 99%

DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In addition, patients with AML and loss of inositol-3-phosphate synthase 1 (ISYNA1) have shown a dependency on extracellular myo-Inositol (Wei et al ., 2020). In this study, the inhibition of the myo-Inositol transporter SLC5A3 was presented as a good proxy for myo-Inositol depletion.…”

Section: Resultsmentioning

confidence: 99%

“…The dependence on L-asparagine in ALL is one paradigmatic example that is used clinically in patients with acute lymphoblastic leukemia. Other ongoing works include cholesterol depletion in lymphoma (Garcia-Bermudez et al ., 2019) and myo-inositol depletion in AML (Wei et al ., 2020), which illustrate that this therapeutic strategy could be exploited in wider settings. All together emphasizes the importance of systematically considering the nutrient environment to target cancer metabolism via synthetic lethality approaches (Muir and Vander Heiden, 2018).…”

Section: Discussionmentioning

confidence: 99%

A network-based approach to integrate nutrient environment in the prediction of synthetic lethality in cancer metabolism

Apaolaza

José‐Eneriz

Valcarcel

et al. 2021

Preprint

View full text Add to dashboard Cite

Synthetic Lethality (SL) is a promising concept in cancer research. A number of computational methods have been developed to predict SL in cancer metabolism, among which our network-based computational approach, based on genetic Minimal Cut Sets (gMCSs), can be found. A major challenge of these approaches to SL is to systematically consider tumor environment, which is particularly relevant in cancer metabolism. Here, we propose a novel definition of SL for cancer metabolism that integrates genetic interactions and nutrient availability in the environment. We extend our gMCSs approach to determine this new family of metabolic synthetic lethal interactions. A computational and experimental proof-of-concept is presented for predicting the lethality of dihydrofolate reductase inhibition in different environments. Finally, our novel approach is applied to identify extracellular nutrient dependences of tumor cells, elucidating cholesterol and myo-inositol depletion as potential vulnerabilities in different malignancies.

show abstract

“…In addition, patients with AML and loss of inositol-3-phosphate synthase 1 (ISYNA1) have shown a dependency on extracellular myo-Inositol [30]. In this study, the inhibition of the myo-Inositol transporter SLC5A3 was presented as a good proxy for myo-Inositol depletion.…”

Section: Extracellular Nutrient Dependences Of Tumor Cellsmentioning

confidence: 88%

“…The dependence on L-asparagine is one paradigmatic example that is used clinically in patients with acute lymphoblastic leukemia. Other ongoing works include cholesterol depletion in lymphoma [29] and myo-Inositol depletion in AML [30], which illustrate that this therapeutic strategy could be exploited in wider settings. All these results together emphasize the importance of systematically considering the nutrient environment to target cancer metabolism via synthetic lethality approaches [32].…”

Section: Discussionmentioning

confidence: 99%

A network-based approach to integrate nutrient microenvironment in the prediction of synthetic lethality in cancer metabolism

et al. 2022

View full text Add to dashboard Cite

Synthetic Lethality (SL) is currently defined as a type of genetic interaction in which the loss of function of either of two genes individually has limited effect in cell viability but inactivation of both genes simultaneously leads to cell death. Given the profound genomic aberrations acquired by tumor cells, which can be systematically identified with -omics data, SL is a promising concept in cancer research. In particular, SL has received much attention in the area of cancer metabolism, due to the fact that relevant functional alterations concentrate on key metabolic pathways that promote cellular proliferation. With the extensive prior knowledge about human metabolic networks, a number of computational methods have been developed to predict SL in cancer metabolism, including the genetic Minimal Cut Sets (gMCSs) approach. A major challenge in the application of SL approaches to cancer metabolism is to systematically integrate tumor microenvironment, given that genetic interactions and nutritional availability are interconnected to support proliferation. Here, we propose a more general definition of SL for cancer metabolism that combines genetic and environmental interactions, namely loss of gene functions and absence of nutrients in the environment. We extend our gMCSs approach to determine this new family of metabolic synthetic lethal interactions. A computational and experimental proof-of-concept is presented for predicting the lethality of dihydrofolate reductase (DHFR) inhibition in different environments. Finally, our approach is applied to identify extracellular nutrient dependences of tumor cells, elucidating cholesterol and myo-inositol depletion as potential vulnerabilities in different malignancies.

show abstract

In vivogenetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia

Cited by 5 publications

References 90 publications

DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation

DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation

A network-based approach to integrate nutrient environment in the prediction of synthetic lethality in cancer metabolism

A network-based approach to integrate nutrient microenvironment in the prediction of synthetic lethality in cancer metabolism

Contact Info

Product

Resources

About