Sarah Skuli, PhD
Decoding Therapeutic Persistence in TP53-Mutant Acute Myeloid Leukemia: From Metabolism to the Microenvironment

TP53-mutant acute myeloid leukemia (AML) is among the most treatment-refractory human malignancies, with poor responses to existing therapies and frequent relapse. Although resistance is often attributed to fixed genetic alterations, emerging evidence suggests that leukemia cells can also survive therapy through dynamic, adaptive cellular states. Our work demonstrates that TP53-mutant AML cells respond to treatment by activating the mevalonate pathway, enhancing antioxidant capacity and mitochondrial fitness. This adaptive response depends on the mevalonate pathway metabolite geranylgeranyl pyrophosphate and its downstream signaling programs, revealing a targetable metabolic vulnerability in therapy-resistant AML.

Building on these findings, our current research focuses on drug-tolerant persister cells: rare, transient cell populations that survive initial therapy and may ultimately seed relapse. We are integrating longitudinal primary patient samples collected before, during, and after treatment with single-cell and spatial multi-omic approaches to define when, where, and how persister states emerge. These studies extend beyond leukemia cell-intrinsic mechanisms to investigate how stromal and immune components of the bone marrow microenvironment create specialized niches that support metabolic adaptation, immune evasion, and survival during therapy. Together, this work seeks to shift therapeutic development from targeting established resistance to identifying and eliminating the cellular states and microenvironmental interactions that sustain therapeutic persistence before relapse occurs.