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

ABSTRACT: Acute leukemias represent deadly malignancies which require better treatment. As challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells. 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. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as essential vulnerability required for survival and growth of different types of acute leukemias in vivo and reconstitution assays in PDX models proved 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. These findings identify ADAM10 as attractive therapeutic target for future treatment of acute leukemias.

INSTRUMENT(S): ultraflex, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Stem Cell, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Ashokkumar Jayavelu  

LAB HEAD: Ashok Kumar Jayavelu

PROVIDER: PXD036223 | Pride | 2023-07-24

REPOSITORIES: Pride