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 -