Despite achieving initial remission, up to 40% of acute myeloid leukemia (AML) patients’ relapse, often without acquiring new genetic mutations. This underscores the role of epigenetic and non-genetic mechanisms in driving minimal residual disease (MRD) and therapy resistance. MRD is thought to arise from a rare subpopulation of cells that evade detection due to their low abundance yet retain the capacity to survive therapy and drive disease recurrence. However, dissecting these rare, therapy resistant clones has been limited by their scarcity, heterogeneity, and lack of defining biomarkers.
To address this, we developed The Clone Claw, a single-cell platform that integrates clonal barcoding, CRISPRa-enabled clone retrieval, and multi-omic profiling (scRNA-seq, scATAC-seq, and spatial transcriptomics). This system enables high-resolution lineage tracing and functional analysis of MRD clones present at frequencies as low as 0.01% across the course of treatment.
We have validated The Clone Claw in AML cell lines and preclinical mouse models, demonstrating its robustness in capturing and characterising rare subclones. Crucially, this platform allows us to isolate and profile MRD populations before, during, and after treatment with clinically relevant targeted agents.
By applying The Clone Claw to longitudinal matched patient samples, we aim to uncover the epigenetic programs and adaptive responses underpinning relapse, insights that have been previously inaccessible with conventional approaches.
This work bridges a critical gap between experimental modelling and clinical translation. By combining cutting-edge single-cell technologies with patient matched samples, our study will advance the mechanistic understanding of AML relapse and pave the way for MRD-guided therapeutic interventions.
This project aligns with the Lorne Cancer Conference’s mission to drive translational research in oncology, offering a new lens into how therapy resistant clones arise, evolve and survive - providing insights into how we might finally target them to improve outcomes for patients with AML.