.tmb-propic-md.jpg?Culture=en&sfvrsn=c25d2b2f_9 "Professor Louis Chesler (Profile pic)")
Scientists have unveiled a ground-breaking approach to tackling one of cancer biology’s most elusive targets: the protein LMO2, a key driver of T-cell acute lymphoblastic leukaemia (T‑ALL).
T‑ALL is a fast-growing cancer of the white blood cells that primarily affects children and young adults. Although survival rates have improved with chemotherapy, relapse remains a major challenge, and targeted therapies are urgently needed.
The researchers behind the current study have introduced a novel platform that should accelerate the discovery of new drugs against LMO2 and other transcription factors – proteins that help control which genes are switched on or off.
This innovation could pave the way for therapies against a class of proteins long considered “undruggable”, offering hope for patients with aggressive forms of leukaemia.
The study was led by scientists at The Institute of Cancer Research, London, and the findings were published in the journal eLife. The work was primarily funded by Blood Cancer UK, with additional funding provided by Cancer Research UK and The Institute of Cancer Research (ICR), which is both a research institute and a charity.
LMO2 is a key target
Among the molecular culprits behind T‑ALL, LMO2 stands out. Its abnormal activation is a hallmark of this disease, with more than half of T-ALL patients having LMO2-expressing tumours. Yet for decades, LMO2 has resisted all attempts at direct drug targeting.
The difficulty lies in LMO2’s structure, or rather, its lack of one. Unlike enzymes or receptors with well-defined shapes, LMO2 is intrinsically disordered, meaning it doesn’t fold into a rigid three-dimensional form. This flexibility, which is essential for LMO2’s biological role, makes it nearly impossible for traditional drugs to latch onto the protein. Conventional small molecules and antibodies rely on binding to stable pockets or surfaces, and they simply cannot get a grip on LMO2.
In healthy cells, LMO2 plays a vital role in blood cell development. It acts as a scaffold, bridging together other proteins – such as TAL1, E47 and GATA factors – into a transcriptional complex that regulates gene expression. In leukaemia, however, LMO2 becomes hijacked by chromosomal rearrangements or mutations that crank up its production. The result is an oncogenic machine that drives uncontrolled cell growth.
Exploiting cellular mechanisms
Until now, dismantling this machine seemed impossible. However, in this study, the researchers have devised a clever workaround: instead of trying to block LMO2’s activity, they set out to destroy it altogether. This strategy hinges on two complementary technologies that exploit the cell’s own waste-disposal system – intracellular antibodies and proteolysis targeting chimeras (PROTACs).
The first approach involves engineering an intracellular antibody fragment, known as an iDAb, that binds tightly to LMO2. This fragment is fused to an E3 ubiquitin ligase, an enzyme that tags proteins for destruction. Once inside the cell, the fusion protein latches onto LMO2 and marks it for degradation by the proteasome, the cell’s protein-recycling machinery. In laboratory tests, this “biodegrader” efficiently eliminated LMO2 from leukaemia cells.
What was particularly interesting was that removing LMO2 didn’t just erase one protein – it caused the entire transcriptional complex to collapse. TAL1 and E47, which depend on LMO2 for stability, were also degraded. This phenomenon, dubbed “collateral breakdown”, amplifies the therapeutic effect: by targeting a single scaffold protein, the strategy can dismantle an entire oncogenic network.
To make the approach more drug-like, the team also developed small molecules called antibody-derived compounds (Abd). These mimic the binding properties of the iDAb and were converted into PROTACs – bifunctional molecules that link the target protein to an E3 ligase.
Like the antibody-based biodegrader, these Abd PROTACs successfully degraded LMO2 in T‑ALL cell lines, triggering programmed cell death. Importantly, cells lacking LMO2 were unaffected, underscoring the specificity of the treatment.
Hope on the horizon
Of course, challenges remain. The current work serves as proof of concept, conducted in cell cultures. Moving towards clinical application will require optimising these molecules for stability, delivery and safety in living organisms. Researchers will need to ensure that the biodegraders do not inadvertently target other proteins and that they can reach leukaemia cells in the body without harming healthy tissues.
Still, the promise is undeniable. Targeted protein degradation is already making waves in drug development, with several PROTAC-based therapies in clinical trials for other diseases. Extending this technology to transcription factors – a class of proteins long considered untouchable – could revolutionise cancer treatment.
For patients with T‑ALL, this research represents hope on the horizon. While much work lies ahead, the ability to target LMO2 marks a turning point. As scientists refine these strategies and take them towards clinical trials, the prospect of more precise, less toxic treatments for leukaemia grows ever closer.
“The implications are profound”
First author Dr Naphannop (Nikki) Sereesongsaeng, Senior Scientific Officer in the Division of Cancer Therapeutics at the ICR, said:
“For decades, intrinsically disordered proteins like LMO2 have been considered beyond the reach of pharmacology. This study shows that targeted degradation can overcome that barrier, even interrupting entire protein complexes.
“We hope that our Abd technology will help other researchers explore this approach to tackling intrinsically disordered proteins – not only in leukaemia and other cancers driven by similar assembles but also in clinical indications such as inflammation, infection and neurological diseases.”
Professor Terence Rabbitts, Group Leader of the Chromosomal Translocations and Intracellular Antibody Therapeutics Group at the ICR, said:
“Beyond its therapeutic potential, the study emphasises susceptible features in cancer biology. It highlights the fragility of oncogenic complexes and suggests that removing a single keystone protein can topple the entire structure. This insight could inspire a new generation of drugs designed not just to inhibit, but to dismantle, the molecular machines that sustain cancer. In particular, the new technology can be applied to tumour-specific chromosomal translocation fusion proteins, which are frequently transcription factors. The implications are profound.”
Focusing on technology development, by combining antibody engineering, chemical innovation and the cell’s own disposal system, researchers have cracked a problem that stymied cancer science for decades. Their achievement is not only a technical triumph but also a glimpse into the future of oncology, where even the most elusive targets can be brought to heel.
Image credit: Pixabay
