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12
Nov
2024

New treatment target for aggressive leukaemia discovered by disrupting its genome organisation

Microscope image of human cells with acute myelocytic leukaemia
 
Image: Human cells with acute myelocytic leukemia (AML) in the pericardial fluid, shown with an esterase stain at 400x. Source: National Cancer Institute (2001)
 

Researchers have identified a key weakness in acute myeloid leukaemia, offering a promising new strategy to delay the progression of this aggressive blood cancer. The discovery focuses on disrupting the function of a certain protein complex that cancer cells, including leukaemia cells, rely on to maintain their abnormal growth.

The research, led by scientists at The Institute of Cancer Research, London, revealed that targeting the nucleosome-remodelling factor (NURF) complex, particularly by inhibiting a specific cancer-driving protein within the complex – BPTF – could provide a new approach to treating acute myeloid leukaemia (AML).

The research, published in The EMBO Journal, was funded by several organisations, including the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreements, the Kirsten and Freddy Johansen Foundation, the Neye Foundation and the Brain Tumour Charity.

Acute myeloid leukaemia remains a challenging cancer to treat

AML’s complexity makes it a challenging cancer to treat due to its diverse genetic mutations, rapid progression and resistance to existing therapies such as chemotherapy and bone marrow transplants, which often come with severe side effects.

The research deepens our understanding of the mechanistic role of the NURF complex, which has previously been studied in other types of cancer but not in AML. Ultimately, the results identify the formation of an alternative, previously unknown, NURF complex and highlight it as a potential drug target in AML.

Experiments in cell cultures, conducted by the research team, show that the disruption of BPTF and the associated NURF complex can impair the leukaemia’s ability to flourish. By clarifying the essential role of BPTF in leukaemia survival, the team hopes to identify and present safer treatment options for patients.

The research provides evidence for a potential therapeutic window to target BPTF and NURF in leukaemia, providing mechanistic insights into how NURF sustains cell growth. BPTF has previously been linked to MYC – another gene well known to promote cancer growth in many other types of cancer. This study offers further insight, showing how the deregulation of NURF can affect the 3D chromatin structure in the cell, including the higher-order chromatin organisation surrounding the MYC gene, altering MYC transcription. It is possible that this mechanism is not specific to leukaemia and is, therefore, relevant for other cancer types.

A new focus for cancer treatment

For the first time, the study shows the formation of an alternative NURF complex with the SMARCA5 gene as its catalytic subunit instead of SMARCA1 – the only recognised catalytic subunit of NURF until this publication. This discovery opens the door for further research into the role of the alternative NURF complex.

The NURF complex plays a crucial role in organising regions of DNA known as insulator regions, where boundaries within the genome help control the growth of leukaemic cells. By disrupting BPTF’s function, the team interfered with this organisation, slowing cancer growth and showing for the first time that this complex regulates insulator regions by directly remodelling these sites.

The researchers also showed that the chromatin reader domains – protein modules that have a role in gene regulation – are necessary neither for the formation of the NURF complex nor the growth of the leukaemic cells. Although they do aid in directing the complex to the chromatin, they are not required for NURF to bind to its specific sites.

New insights could lead to targeted therapies

Dr Alex Radzisheuskaya, Leader of the Chromatin Biology Group at the ICR and co-corresponding author, said:

“We hope this research provides hope to people affected by acute myeloid leukaemia by revealing a potential new target for cancer treatment that doesn’t rely on conventional approaches. Instead, therapies could now focus on interfering with the NURF complex’s ability to organise the cancer genome, effectively hindering its growth at a fundamental level. Our early findings suggest that such an approach could effectively destroy cancer while being less harmful to normal cells, which is crucial in reducing side effects for patients.”

Dr Isabel Peña Rømer, Postdoctoral Training Fellow in the Epigenetics and Cancer Group at the ICR and shared first author of the study, said:

“We have discovered that not all parts of the BPTF are equally important for the survival of acute myeloid leukaemia, demonstrating that some well-studied regions, previously thought to be essential, were dispensable. This new insight could help us formulate specific treatments that target BPTF more effectively, allowing for a therapeutic window where we impact cancer progression, while potentially minimising unintended impacts on healthy cells.

“Given the urgent need for new therapies to treat this devastating disease, this discovery provides mechanistic insights that could be exploited for leukaemia treatment and beyond.”

A new understanding of cancer’s manipulation

Professor Kristian Helin, Chief Executive Officer of the ICR and co-corresponding author of this study, said:

"This research presents a new understanding of how cancer cells exploit their environment to survive. In the short term, our finding that AML cells can thrive without the BPTF chromatin reader domain has weakened the premise for the recent efforts to target BPTF domains with small molecules for cancer treatment. Instead, the study indicates that efforts should focus on other domains of BPTF or consider the deletion of the entire complex."This research showcases the importance of fundamental biology for our translational research ambitions, taking us a step closer to developing new therapies that not only halt the progression of this aggressive disease but also improve the quality of life for patients.”

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leukaemia blood cancer acute myeloid leukaemia Alex Radzisheuskaya
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