Tracking The Molecular Dynamics of Lineage Switch Under CD19 CAR-T Treatment in Non-KMT2A Rearranged B-ALL Patients

Abstract Lineage switch in B-acute lymphoblastic leukemia (B-ALL) patients is a rare event during CD19 chimeric antigen receptor (CAR)-T treatment. Some studies have reported KMT2A rearrangements (KMT2A-r) as a risk factor in lineage switch, but the underlying mechanism of non-KMT2A-r cases remains unclear. Here, we described two young adult B-ALL lineage switch cases without KMT2A-r. Our analysis revealed lineage-specific transcription factors and surface markers related alterations, while major gene mutations remain unchanged. By reconstructing developmental trajectories, B-progenitor-like blasts were found to be reprogrammed into myeloid blasts after CAR-T treatment. Interestingly, we observed the increase of BCOR/BCORL1 truncating mutation burden at myeloid relapse in both cases. By retrospective analysis, we found that BCOR/BCORL1 gene mutated patients possessed myeloid-related features, indicating it as a potential risk factor for lineage switch. In summary, we established a study paradigm about lineage switch by single-cell technologies, which may be applied to clinical practice.