Downregulating a specific protein slows down the development of acute myeloid leukaemia (AML), a malignant and very aggressive blood disorder that has no optimal treatment. This discovery helps researchers to understand how the body’s cells regulate which parts of the DNA can be read and which cannot.
In searching for new types of drugs that can treat AML, researchers made a useful discovery: inhibiting a specific protein in mice slows down the development of AML and enables them to live much longer.
The discovery, which could pave the way for developing new drugs to combat AML, also gives researchers a window into the cellular machinery and improves understanding of how genes are expressed – or not.
“For 45 years, the standard treatment for people with AML has not changed, with only 24% surviving for five years. We need new types of treatment and have identified a new drug target that has shown promising results in preclinical studies,” explains a researcher behind the study, Kristian Helin, Professor, Chief Executive and President, Institute of Cancer Research, London, United Kingdom.
The research has been published in The EMBO Journal.
AML still has very poor prognosis
AML is a malignant blood disorder characterised by genetic dysregulation of the blood cells, resulting in uncontrolled proliferation of myeloid progenitors in the bone marrow and peripheral blood.
This reduces the production of healthy blood cells, and once the cancer cells enter the bloodstream, the cancer can spread throughout the body.
The treatment for AML has remained largely the same for the past 45 years and involves chemotherapy, but survival rates remain poor despite recent therapeutic advances.
Kristian Helin and colleagues therefore aimed to identify new cellular targets for developing drugs to combat AML.
He explains that finding new targets to combat cancer ideally results in identifying proteins that are only present in or overexpressed in AML.
“Most drug targets are also important for other cells, so the key is finding targets for attacking the cancer cells without having too many side-effects, including on the body’s own cells,” says Kristian Helin.
Disabling thousands of genes
The researchers developed a mouse model for AML and then performed CRISPR screening on AML cells, knocking out several thousand genes one at a time.
The screening enabled them to identify many genes that seemed to affect the cancer’s growth and the potential for survival.
Good drug targets cause the cancer cells to die or stop dividing when a given gene – and thus also the protein that the gene codes for – is disabled.
In the screening, the researchers identified several genes that are necessary for AML cell growth and focused on those that did not appear to disable healthy cells.
“We identified many genes and validated them one at a time. Then we needed to find some genes that seemed to influence the growth of leukaemia cells more than healthy cells,” explains Kristian Helin.
BPTF protein could become a new therapeutic target
The researchers identified the bromodomain PHD finger transcription factor (BPTF), a subunit of the nucleosome remodelling factor (NURF) complex, as a potential drug target for future treatment of people with AML.
Mice with AML lived much longer if the researchers disabled BPTF.
The researchers also aimed at determining the function of BPTF. These studies showed that it regulates the accessibility of chromatin. Chromatin consists of DNA and associated proteins, and the associated proteins compact the more than two-metre-long DNA into a well-organised structure inside a cell.
If DNA were folded arbitrarily, various cellular mechanisms could not read the genes, but BPTF ensures that the cellular mechanisms have access to the relevant genes at relevant times.
Kristian Helin says that BPTF is interesting in relation to AML because it helps to ensure that the cancer cells can express the gene MYC, a classic oncogene involved in different types of cancer, with high expression of MYC ensuring the rapid proliferation of cancer cells.
When BPTF is disabled, the chromatin around the MYC gene is not accessible, and therefore the cancer cells cannot express the necessary amount of MYC to ensure optimal conditions for the cancer cells.
“For many years, cancer researchers and the pharmaceutical industry have tried to develop drugs that target MYC itself, but this has not yet been successful. Targeting a protein with a drug to inhibit its activity requires that the protein has a pocket to which inhibitors can attach. MYC does not have such a pocket, but BPTF does. Therefore, targeting BPTF could be an alternative to targeting MYC in cancers in which MYC plays a role, including AML,” says Kristian Helin.
The theory also proved to be valid in practice, since the cancer cells perished, and the mice lived longer when the researchers downregulated BPTF.
Basic scientific discovery has more immediate impact
Kristian Helin says that discovering a new potential target for AML may be the study’s secondary objective, since the final success of this discovery would be developing specific inhibitors that can be approved for treatment.
The primary advance may therefore be improved understanding of how the chromatin structure is regulated.
The researchers have obtained new basic scientific insight into how cells make genes accessible or inaccessible.
NURF comprises four proteins, each with its own separate chromatin-regulating function.
One protein opens the chromatin structure so that the genes are exposed. BPTF determines where the chromatin structure should be opened.
“This study advances knowledge on how to open the chromatin structure and the side-effects of cells being unable to perform this function. For the cancer cells, this inhibits cell proliferation or causes cell death. This makes the discovery useful for possible treatment of AML,” concludes Kristian Helin.
