Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy
<jats:title>Abstract</jats:title><jats:p>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 sough...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/133547 |
| _version_ | 1826215502646607872 |
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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 | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>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.</jats:p> |
| first_indexed | 2024-09-23T16:32:12Z |
| format | Article |
| id | mit-1721.1/133547 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:32:12Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1335472021-10-28T03:09:47Z 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 <jats:title>Abstract</jats:title><jats:p>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.</jats:p> 2021-10-27T19:53:28Z 2021-10-27T19:53:28Z 2021-08-02 2021-08-03T16:01:02Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133547 en 10.1038/s41375-021-01361-8 Leukemia Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | 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 |
| url | https://hdl.handle.net/1721.1/133547 |
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