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Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy
Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807390/ https://www.ncbi.nlm.nih.gov/pubmed/34341479 http://dx.doi.org/10.1038/s41375-021-01361-8 |
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author | Pikman, Yana Ocasio-Martinez, Nicole Alexe, Gabriela Dimitrov, Boris Kitara, Samuel Diehl, Frances F. Robichaud, Amanda L. Conway, Amy Saur Ross, Linda Su, Angela Ling, Frank Qi, Jun Roti, Giovanni Lewis, Caroline A. Puissant, Alexandre Vander Heiden, Matthew G. Stegmaier, Kimberly |
author_facet | Pikman, Yana Ocasio-Martinez, Nicole Alexe, Gabriela Dimitrov, Boris Kitara, Samuel Diehl, Frances F. Robichaud, Amanda L. Conway, Amy Saur Ross, Linda Su, Angela Ling, Frank Qi, Jun Roti, Giovanni Lewis, Caroline A. Puissant, Alexandre Vander Heiden, Matthew G. Stegmaier, Kimberly |
author_sort | Pikman, Yana |
collection | PubMed |
description | Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers. |
format | Online Article Text |
id | pubmed-8807390 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88073902022-02-03 Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy Pikman, Yana Ocasio-Martinez, Nicole Alexe, Gabriela Dimitrov, Boris Kitara, Samuel Diehl, Frances F. Robichaud, Amanda L. Conway, Amy Saur Ross, Linda Su, Angela Ling, Frank Qi, Jun Roti, Giovanni Lewis, Caroline A. Puissant, Alexandre Vander Heiden, Matthew G. Stegmaier, Kimberly Leukemia Article Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers. Nature Publishing Group UK 2021-08-02 2022 /pmc/articles/PMC8807390/ /pubmed/34341479 http://dx.doi.org/10.1038/s41375-021-01361-8 Text en © The Author(s), under exclusive licence to Springer Nature Limited 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Pikman, Yana Ocasio-Martinez, Nicole Alexe, Gabriela Dimitrov, Boris Kitara, Samuel Diehl, Frances F. Robichaud, Amanda L. Conway, Amy Saur Ross, Linda Su, Angela Ling, Frank Qi, Jun Roti, Giovanni Lewis, Caroline A. Puissant, Alexandre Vander Heiden, Matthew G. Stegmaier, Kimberly Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy |
title | Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy |
title_full | Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy |
title_fullStr | Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy |
title_full_unstemmed | Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy |
title_short | Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy |
title_sort | targeting serine hydroxymethyltransferases 1 and 2 for t-cell acute lymphoblastic leukemia therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807390/ https://www.ncbi.nlm.nih.gov/pubmed/34341479 http://dx.doi.org/10.1038/s41375-021-01361-8 |
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