Functional identification and targeting of zinc-finger containing proteins at domain resolution in leukemia

Genes encoding zinc finger (ZnF) proteins are often aberrantly expressed and/or mutated in acute myeloid leukemia (AML). Dysregulation of these factors can lead to disruption of normal hematopoiesis and promotes leukemogenesis. The prototypic ZnF is a small domain consisting of cysteine and histidine residues that coordinate one or more zinc ions. This structure enables their function to promote direct interaction with DNA, RNA and proteins and the regulation of various cellular processes. Importantly, ZnF domains are emerging drug targets, like in targeted protein degradation by thalidomide analogs. We hypothesize that identifying ZnF domains critical for AML cell growth will provide new entry points for the design of novel therapeutic strategies. In this project, we conduct a base-editor screen targeting all cysteine and histidine residues within all ZnF domains of all human ZnF proteins. We will validate the role of candidate ZnF domains, interaction partners and underlying mechanisms in AML. This will provide insights into the domain-specific functions of ZnF proteins and enable the development of chemical strategies to target specific domains ZnF proteins in AML.

Publication History

Article published online:
09 May 2025