Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo
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Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo. / Bahrami, Ehsan; Schmid, Jan Philipp; Jurinovic, Vindi; Becker, Martin; Wirth, Anna-Katharina; Ludwig, Romina; Kreissig, Sophie; Duque Angel, Tania Vanessa; Amend, Diana; Hunt, Katharina; Öllinger, Rupert; Rad, Roland; Frenz, Joris Maximilian; Solovey, Maria; Ziemann, Frank; Mann, Matthias; Vick, Binje; Wichmann, Christian; Herold, Tobias; Jayavelu, Ashok Kumar; Jeremias, Irmela.
I: Molecular Cancer, Bind 22, Nr. 1, 08.07.2023, s. 107.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo
AU - Bahrami, Ehsan
AU - Schmid, Jan Philipp
AU - Jurinovic, Vindi
AU - Becker, Martin
AU - Wirth, Anna-Katharina
AU - Ludwig, Romina
AU - Kreissig, Sophie
AU - Duque Angel, Tania Vanessa
AU - Amend, Diana
AU - Hunt, Katharina
AU - Öllinger, Rupert
AU - Rad, Roland
AU - Frenz, Joris Maximilian
AU - Solovey, Maria
AU - Ziemann, Frank
AU - Mann, Matthias
AU - Vick, Binje
AU - Wichmann, Christian
AU - Herold, Tobias
AU - Jayavelu, Ashok Kumar
AU - Jeremias, Irmela
N1 - © 2023. The Author(s).
PY - 2023/7/8
Y1 - 2023/7/8
N2 - 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.
AB - 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.
KW - Humans
KW - Mice
KW - Animals
KW - ADAM10 Protein/genetics
KW - Proteomics
KW - CRISPR-Cas Systems
KW - Membrane Proteins/genetics
KW - Leukemia/genetics
KW - Disease Models, Animal
KW - Tumor Microenvironment
KW - Amyloid Precursor Protein Secretases/genetics
U2 - 10.1186/s12943-023-01803-0
DO - 10.1186/s12943-023-01803-0
M3 - Journal article
C2 - 37422628
VL - 22
SP - 107
JO - Molecular Cancer
JF - Molecular Cancer
SN - 1476-4598
IS - 1
ER -
ID: 402759540