Degradation of LMO2 in T cell leukaemia results in collateral breakdown of transcription complex partners and causes LMO2-dependent apoptosis

Journal article

LMO2 is an intrinsically disordered transcription factor activated in T cell leukaemia that is difficult to target. It forms part of a multi-protein complex that has bipartite DNA binding through heterodimeric basic-helix-loop-helix (bHLH) and GATA proteins. To determine if degradation of LMO2 in the context of T cell acute leukaemias (T-ALL) has therapeutic potential, a chimeric intracellular antibody has been developed fusing an anti-LMO2 single-domain variable region with one of three E3 ligases to create biodegraders. The intracellular binary interaction of these biodegraders with LMO2 leads to its proteasomal degradation but, in addition, concomitant loss of bHLH proteins that associate with LMO2 in the DNA-binding complex. Chemical compound surrogates of the intracellular antibody paratope (called antibody-derived [Abd] compounds) have been modified to create proteolysis targeting chimeras (PROTACs) for orthogonal assays of effects of LMO2 degradation. These form a ternary complex with LMO2 and E3 ligase in leukaemia cells that induces degradation of LMO2 and is also accompanied by loss of associated bHLH proteins. This is accompanied by T-ALL growth inhibition, alterations in proteins involved in cell cycling and instigation of apoptosis. These effects do not occur in the absence of LMO2. Our work demonstrates that degradation of LMO2 affects T-ALL, and the lead compounds can eventually be developed into drugs for patient treatment. Our work describes methods for drug discovery starting with antibody fragments.

Authors: Sereesongsaeng, N; Bataille, C; Russell, A; Bery, N; Sialana, FJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: eLife Sciences Publications
• Journal: eLife
• Volume: 14
• Article number: RP106699
• Publication date: 2025-12-12
• DOI: 10.7554/elife.106699
• EISSN: 2050-084X
• ISSN: 2050-084X
• Language: English
• Keywords: biodegrader; transcription factor; Mouse; chromosomal translocation; intracellular antibody; PROTAC; T cell leukaemia