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Bahrami, E. ; Schmid, J.P. ; Jurinovic, V. ; Becker, M. ; Wirth, A.-K. ; Ludwig, R. ; Kreissig, S.* ; Duque Angel, T.V. ; Amend, D. ; Hunt, K. ; Öllinger, R.* ; Rad, R.* ; Frenz, J.M.* ; Solovey, M. ; Ziemann, F.* ; Mann, M.* ; Vick, B. ; Wichmann, C.* ; Herold, T. ; Jayavelu, A.K.* ; Jeremias, I.

Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo.

Mol. Cancer 22:107 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adam10 ; Acute Leukemia ; Crispr-cas9 In Vivo Screen ; Leukemia Stem Cells ; Pdx ; Proteomics; Acute Lymphoblastic-leukemia; Stem-cells; Xenograft Models; Cancer; Expression; Cxcr4; System; Family
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
e-ISSN 1476-4598
Zeitschrift Molecular Cancer
Quellenangaben Band: 22, Heft: 1, Seiten: , Artikelnummer: 107 Supplement: ,
Verlag BioMed Central
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Institute of Computational Biology (ICB)
POF Topic(s) 30204 - Cell Programming and Repair
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Stem Cell and Neuroscience
Enabling and Novel Technologies
PSP-Element(e) G-506600-001
G-554200-001
DOI 10.1186/s12943-023-01803-0
WOS ID 001022442200001
Scopus ID 85164269592
PubMed ID 37422628
Erfassungsdatum 2023-10-06
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