S105: CLONAL DIFFERENTIATION TRAJECTORIES OF ADULT ACUTE LYMPHOBLASTIC LEUKEMIA AT SINGLE CELL LEVEL

• DOI: 10.1097/01.hs9.0000967332.12393.2c
• Publication Date: 2023-08-08T13:01:28Z
• Authors: Alec Geßner; Adrien Jolly; Tjeerd Sijmonsma; Weijia Yu; Khalil Abou-El-Ardat; Manuel Kaulich; Stefan Guenther; Fabian Lang; Florian Buettner; Michael Rieger
• Keywords: Acute lymphocytic leukemia

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: While remission rates are >90% after first-line therapy in adult B-cell precursor acute (BCP-ALL), the prognosis relapse is dismal with survival under 10%. Relapse may arise from remaining therapy-resistant leukemia-initiating cells (LICs) exhibiting specific gene expression pattern. Aims: Consequently, identification of cellular architecture and phenotypical plasticity BCP-ALL vivo key importance development successful treatment strategies. Methods: To investigate subclonal architecture, clonal interference differentiation trajectories BCP-ALL, we developed complex genetic barcoding systems at genomic transcriptomic level to track individual LICs their progeny. Thereby, can detect single-cell barcode together mRNAs >50 surface markers using CITE-Seq. We transduced established patient-derived primary B-ALLs (PDLTCs) lentiviral constructs analyzed leukemic before transplantation leukemogenesis NSG mice different organ locations. majority freshly PDLTCs homed engrafted murine bone marrow spleen seven days transplantation, only a few hundred clones seemed remain full-blown leukemia. Dominant subclones demonstrated strong local expansion accounting for most tumor mass, whereas hundreds small persisted throughout disease without expansion. Results: Single-cell RNA-Seq revealed that several weeks transduction construct, transcriptomes carrying an identical were highly correlated. This self-renewal memory conserved across multiple generations. Furthermore, single cell molecular profile barcoded isolated showed undergo thereby phenotypes be observed. After transplanting same pool stably into mice, numerous barcodes detected more than one mouse; strikingly harboring found exhibit similar patterns animals. result indicates have intrinsic properties. validate states derived scCITE-Seq, transplanted prospectively subpopulations NSGs. Thereby particular associated delayed initiation differential engraftment disease. Summary/Conclusion: Overall, our work suggests hierarchy limited number LICs. These results consequences on understanding pathology future capabilities versus influence environment establishment these will perform whole imaging spatial transcriptomics determine localization association niche components. Keywords: Bone Marrow, Clonality, B