Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo
Background Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. Methods To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo. Results A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo. Conclusions These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias..
Highlights - Ultra-deep proteomics of minute leukemia stem cells uncovers increased cell adhesion. - In vivo PDX CRISPR-Cas9 screens identify ADAM10 as essential for leukemia in mice. - ADAM10 knockout impairs the leukemia-niche interaction and stem cell numbers. - Therapeutic targeting of ADAM10 reduces PDX leukemia fitness and augments therapy..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Molecular cancer - 22(2023), 1 vom: 08. Juli |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bahrami, Ehsan [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
ADAM10 |
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| Anmerkungen: |
© The Author(s) 2023 |
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| doi: |
10.1186/s12943-023-01803-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Background Acute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. Methods To identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo. Results A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo. Conclusions These findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias. | ||
| 520 | |a Highlights - Ultra-deep proteomics of minute leukemia stem cells uncovers increased cell adhesion. - In vivo PDX CRISPR-Cas9 screens identify ADAM10 as essential for leukemia in mice. - ADAM10 knockout impairs the leukemia-niche interaction and stem cell numbers. - Therapeutic targeting of ADAM10 reduces PDX leukemia fitness and augments therapy. | ||
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| 650 | 4 | |a Leukemia stem cells | |
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