Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells
High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2023
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| Online Access: | https://hdl.handle.net/1721.1/147849 |
| _version_ | 1826191113524871168 |
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| author | Morris, Vivian Wang, Dahai Li, Zhiheng Marion, William Hughes, Travis Sousa, Patricia Harada, Taku Sui, Shannan Ho Naumenko, Sergey Kalfon, Jérémie Sensharma, Prerana Falchetti, Marcelo Vinicius da Silva, Renan Candelli, Tito Schneider, Pauline Margaritis, Thanasis Holstege, Frank CP Pikman, Yana Harris, Marian Stam, Ronald W Orkin, Stuart H Koehler, Angela N Shalek, Alex K North, Trista E Pimkin, Maxim Daley, George Q Lummertz da Rocha, Edroaldo Rowe, R Grant |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Morris, Vivian Wang, Dahai Li, Zhiheng Marion, William Hughes, Travis Sousa, Patricia Harada, Taku Sui, Shannan Ho Naumenko, Sergey Kalfon, Jérémie Sensharma, Prerana Falchetti, Marcelo Vinicius da Silva, Renan Candelli, Tito Schneider, Pauline Margaritis, Thanasis Holstege, Frank CP Pikman, Yana Harris, Marian Stam, Ronald W Orkin, Stuart H Koehler, Angela N Shalek, Alex K North, Trista E Pimkin, Maxim Daley, George Q Lummertz da Rocha, Edroaldo Rowe, R Grant |
| author_sort | Morris, Vivian |
| collection | MIT |
| description | High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-r B-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis. |
| first_indexed | 2024-09-23T08:50:27Z |
| format | Article |
| id | mit-1721.1/147849 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:50:27Z |
| publishDate | 2023 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1478492023-02-03T03:48:55Z Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells Morris, Vivian Wang, Dahai Li, Zhiheng Marion, William Hughes, Travis Sousa, Patricia Harada, Taku Sui, Shannan Ho Naumenko, Sergey Kalfon, Jérémie Sensharma, Prerana Falchetti, Marcelo Vinicius da Silva, Renan Candelli, Tito Schneider, Pauline Margaritis, Thanasis Holstege, Frank CP Pikman, Yana Harris, Marian Stam, Ronald W Orkin, Stuart H Koehler, Angela N Shalek, Alex K North, Trista E Pimkin, Maxim Daley, George Q Lummertz da Rocha, Edroaldo Rowe, R Grant Massachusetts Institute of Technology. Department of Biological Engineering High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-r B-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis. 2023-02-02T19:03:58Z 2023-02-02T19:03:58Z 2022 2023-02-02T18:49:58Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147849 Morris, Vivian, Wang, Dahai, Li, Zhiheng, Marion, William, Hughes, Travis et al. 2022. "Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells." Cell Reports, 39 (4). en 10.1016/J.CELREP.2022.110752 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Morris, Vivian Wang, Dahai Li, Zhiheng Marion, William Hughes, Travis Sousa, Patricia Harada, Taku Sui, Shannan Ho Naumenko, Sergey Kalfon, Jérémie Sensharma, Prerana Falchetti, Marcelo Vinicius da Silva, Renan Candelli, Tito Schneider, Pauline Margaritis, Thanasis Holstege, Frank CP Pikman, Yana Harris, Marian Stam, Ronald W Orkin, Stuart H Koehler, Angela N Shalek, Alex K North, Trista E Pimkin, Maxim Daley, George Q Lummertz da Rocha, Edroaldo Rowe, R Grant Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells |
| title | Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells |
| title_full | Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells |
| title_fullStr | Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells |
| title_full_unstemmed | Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells |
| title_short | Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells |
| title_sort | hypoxic glycolytic metabolism is a vulnerability of b acute lymphoblastic leukemia initiating cells |
| url | https://hdl.handle.net/1721.1/147849 |
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