Moennig, M. | bioRxiv Science

bioRxiv2026

Multiscale biological interactions define clinical trajectories in acute myeloid leukemia

Cancer is characterized by complex interactions across genetic, cellular, and microenvironmental scales. However, a quantitative understanding of how these interactions shape clinical trajectories remains limited. Here, we present a multi-scale single-cell dataset from 184 treatment-naive acute myeloid leukemia (AML) patients spanning all major genetic subtypes, together with an analytical framework to dissect interactions across biological scales. We show that distinct clinical outcomes are encoded by specific cross-scale, cross-compartment interactions present at diagnosis: response to induction therapy is governed by interactions between genetic alterations and leukemic differentiation state; relapse following chemotherapy is associated with non-genetic programs linked to metabolism; and relapse after allogeneic stem cell transplantation is driven by interactions between the immune microenvironment and residual healthy hematopoiesis. Together, our study provides a framework to resolve intra- and inter-patient heterogeneity in cancer and supports a model in which clinical trajectories in AML emerge from defined interactions across biological scales.

cancer biology↗

bioRxiv2024

Integrated scFv identification and CAR T cell generation for AML targeting in vivo

Cancer immunotherapy has witnessed remarkable advancements, especially in the development of chimeric antigen receptor (CAR) T cell therapy. Here, we integrated single-chain variable fragment (scFv) development with CAR T cell generation based on a newly developed scFv phagemid library. High-throughput long-read PacBio sequencing identified 4.5 x 107 unique full-length scFv proteins within the generated library. In a proof of principle, we screened for scFvs targeting C-type lectin-like molecule-1 (CLL1) with subsequent cloning into a third generation retroviral CAR backbone. Functional assays revealed the specificity and potency of these CAR T cells in targeting CLL1-positive AML cells in vitro. In vivo studies reduced tumor burden and improved survival rates compared to controls. Taken together, screening for tumor specific scFvs against CLL1 can rapidly generate AML specific CAR T cells with effective tumor killing in vivo.

immunology↗