30 Oct 2024

Research blog: DNA, focal deletions and leukaemia

Inside the nucleus of our cells, DNA folds and forms loops that play a critical role in gene regulation—turning genes on or off. Genes are segments of DNA composed of sequences of nucleotides, thousands of genes in turn make up chromosomes which are structures that organise and package DNA. DNA is made up of 23 pairs of chromosomes and each of these contains thousands of genes. In cancer cells, however, this DNA frequently undergoes abnormal cutting and rejoining, resulting in a phenomenon known as “focal deletion.” To grasp the significance of these alterations, we must first examine the components that make up DNA.

Think of DNA like an instruction manual for our bodies, guiding how our cells grow and function. Genes provide the direct instructions to make proteins, which handle important jobs like repairing cells or fighting infections. Other parts, known as “noncoding” regions, don’t make proteins themselves but act like switches, turning genes on or off at the right times. When these switches break or get deleted, it can lead to diseases like T-cell acute lymphoblastic leukaemia (T-ALL).

While cancer research often focuses on changes (mutations) in the protein-making parts of genes, there’s another way cancer can initiate changes in the noncoding regions. These subtle changes don’t alter the proteins directly but affect the switches controlling whether the genes are switched on and off. One example is something called “enhancer hijacking,” where a broken switch can mistakenly turn on a cancer-causing gene, leading to uncontrolled cell growth which is a key feature in cancer.

A new international study published in the prestigious journal, Blood, led by a previously funded Leukaemia UK John Goldman Fellow and his then supervisor:  Dr Sunniyat Rahman and Prof. Marc Mansour, UCL, has uncovered how small deletions in noncoding DNA, called focal deletions, can drive the development of T-ALL by activating a gene known as IRX3. Let’s break down what this means and why it matters.

The role of DNA’s “noncoding” regions

Between the important instructions (genes) within our manual (DNA), there are noncoding regions that act as footnotes. They don’t make anything themselves but tell the important instructions when to get to work. Among these noncoding regions are enhancers—special DNA sequences that help boost the activity of specific genes. Other sections, called boundary elements, act like fences, making sure enhancers only activate the correct genes.

Normally, this system works like a well-organized production line. But when something disturbs these boundaries, enhancers can activate the wrong genes, which is when things can go wrong— like telling a gene that should stop growing to keep multiplying, potentially leading to cancer.

Focal deletions in T-ALL: 

T-ALL is a type of cancer that affects T cells, a kind of white blood cell. The new research from Dr Rahman and his colleagues focused on how small, specific deletions in noncoding DNA can cause problems in T-ALL. These deletions don’t affect the genes themselves but instead remove critical regulatory elements in a region that wasn’t previously linked to cancer.

The researchers discovered that these focal deletions occur in a gene called FTO. Specifically, these deletions happen in a part of the gene that doesn’t make proteins but plays a role in regulating other genes. These small deletions are found in about 6.2% of children and 1.5% of adults with T-ALL, so while they’re not common, they’re significant.

These deletions remove a binding site for a protein called CTCF, which normally keeps enhancers in check. Without CTCF, a nearby enhancer can “hijack” a gene called IRX3, activating it inappropriately. IRX3 is an oncogene, which means when it gets turned on at the wrong time, it can promote cancer cell growth.

This study reveals a new way that cancer can develop, especially in T-ALL, by showing how noncoding regions of DNA can play a crucial role in controlling gene activity. The focal deletions in the FTO gene are now recognized as an unexpected driver of cancer, highlighting how important these noncoding regions are for keeping our cells in check.

Understanding this mechanism also opens up new possibilities for studying other cancers. It suggests that there may be other genes, like IRX3, that are normally kept off by being “tethered” to noncoding DNA regions. When this tethering is disrupted, it might lead to cancer development.

While this research provides exciting new insights, it also raises important questions. Could targeting the IRX3 gene or the pathways that regulate it offer new treatments for T-ALL? Could these small focal deletions serve as markers to help detect T-ALL earlier or monitor its progression?

Though more research is needed, this study is a major step forward in understanding T-ALL and how small changes in noncoding DNA can influence cancer. By continuing to explore these mechanisms, scientists may uncover new strategies to diagnose, treat, or even prevent cancers caused by enhancer hijacking.

Conclusion

This study shows how even small changes in the noncoding regions of our DNA can have big consequences, leading to the activation of cancer genes like IRX3. The discovery of focal deletions in the FTO gene highlights just how important these “switches” are in controlling gene activity and keeping cancer at bay. As scientists continue to unravel the mysteries of these noncoding regions, we move closer to finding better ways to fight cancers like T-ALL.

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References:

Rahman S, Bloye G, Farah N, Demeulemeester J, Costa JR, O’Connor D, Pocock R, Rapoz-D’Silva T, Turna A, Wang L, Lee SW, Fielding AK, Roels J, Jaksik R, Dawidowska M, Van Vlierberghe P, Hadjur S, Hughes JR, Davies J, Gutierrez A, Kelliher M, Van Loo P, Dawson MA, Mansour MR. Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia. Blood. 2024 Sep 24:blood.2024024300. doi: 10.1182/blood.2024024300. Epub ahead of print. PMID: 39316719.