ADAM10’s Sheddase Function Augments the Interaction of Leukemia Cells with the Bone Marrow Niche in PDX Models in Vivo

Interrupting tumor-microenvironment interactions is an attractive therapeutic strategy. We developed a CRISPR-Cas9 screening approach for functional analysis of surface molecules in patient-derived xenograft (PDX) acute leukemia (AL) models in vivo in order to decipher tumor specific vulnerabilities. A customized library was run in 2 AL PDX samples and candidates were confirmed using a competitive in vivo approach. ADAM10 was depleted in both and validated in 6 PDX models. Treating PDX cells with ADAM10 inhibitor reduced the bone marrow (BM) engraftment capacity, while KO of ADAM10 reduced the leukemia stem cell frequency. Both AML and ALL ADAM10 KO PDX samples showed increased sensitivity towards routine chemotherapy in vivo. Reconstitution of ADAM10 KO PDX cells with a WT variant in vivo rescued the phenotype, while an enzymatic domain lacking variant did not, highlighting the importance of ADAM10’s sheddase function. In conclusion, we established CRISPR-Cas9 drop-out screens in PDX models in vivo to explore patient-specific tumor dependencies. Our data revealed ADAM10’s role in maintaining leukemic cells in the BM niche, thus representing an attractive future therapeutic target.