Back row, left to right: Daniel Aron Ang, Jean-Michel Carter
Front row, left to right: Nanyang Assistant Professor Li Yinghui, Kamalakshi Deka
Researchers from the NTU School of Biological Sciences (SBS) have demonstrated for the first time in multiple myeloma that a protein, p52, produced from the hyperactivation of a genetic signalling pathway known as NF-κB, reprogrammes DNA regions to express genes that drive the growth and survival of cancer cells in the disease. Their research paves the way for the development of new cancer treatment options that target the genes in cancer cells that are regulated by p52.You can read their full paper here.
Multiple myeloma
There are several kinds of blood cancers like leukaemia, which affects the bone marrow, and lymphoma, which targets the lymphatic system. Multiple myeloma is another kind of blood cancer that specifically affects the plasma cells in blood. Not to be confused with blood plasma, which is a light yellowish fluid that makes up for around 55 percent of our blood and contains proteins like fibrinogen that helps our blood to clot, plasma cells are a type of white blood cell responsible for producing antibodies that fight off infections.
The disease is known as multiple myeloma due to the multiple areas or patches of cancer cells in the bone marrow that would have appeared by the time patients are diagnosed. When these cancerous plasma cells grow out of control in the bone marrow, they crowd out other healthy blood cells and hinder their usual functions.
Cancerous plasma cells also produce a high level of M-proteins, or monoclonal immunoglobin, a particular type of antibody. In healthy circumstances, antibodies come in a balanced variety of types in order to fight off infections. However, these M-proteins are identical in structure, hence the term ’monoclonal,’ and are only able to target a particular antigen, a substance that triggers an immune response. At higher levels, they prevent the immune system as a whole from dealing with infections. This is why multiple myeloma patients tend to suffer from frequent infections that can turn deadly, amongst other symptoms.
Globally, multiple myeloma is the second most prevalent blood cancer and accounts for more than 100,000 deaths per year, with a median survival rate of 6 years. The main challenge facing effective treatment is the genetic heterogeneity of this disease. Genetic abnormalities can vary not only between patients, but also within the same patient over time, making it difficult to develop effective treatments that can handle such a wide range of genetic abnormalities.
The importance of the NF-κB signalling pathway
In biology, a pathway refers to a series of molecular interactions at a cellular level that results in specific outcomes or responses, and scientists often describe these pathways as being canonical or non-canonical. Describing a pathway as canonical shows that it is the “standard,” or most common way, with which a cell responds to stimuli, while calling it a non-canonical pathway demonstrates that it is the less common, or alternate, mechanism via which a cell responds.
The nuclear factor kappa B, or NF-κB, pathway, results in the production of NF-κB proteins, and comprises of canonical and non-canonical branches. Both branches play important roles in the human immune system. In general terms, the canonical NF-κB pathway regulates inflammatory responses, cell survival and proliferation, while the non-canonical NF-κB pathway helps in the development of immune cells and maintains balance in the immune system. NF-κB binds to specific regions of the cell’s DNA, activating or suppressing the expression of genes that, in turn, activate the cell’s immune response.
In healthy circumstances, both NF-κB pathways are activated only when needed. However, in cancer cells, both pathways can be constantly activated, switching on genes that promote cell proliferation and prevent programmed cell death, or apoptosis, resulting in uncontrolled cell growth.
The team of scientists at NTU SBS, led by Nanyang Assistant Professor Li Yinghui, have observed that recurrent mutations, particularly in multiple myeloma cases, have led to the hyperactivation of the non-canonical NF-κB pathway, and these mutations have also resulted in higher incidences of relapse or refractory cases.
The p52 protein and future cancer therapeutics
The constant activation of the non-canonical NF-κB pathway causes a specific form of the NF-κB protein to be produced, known as p52. Prof Li’s team at SBS is the first to demonstrate that p52 can reprogramme a cell’s DNA to support cancer cell growth and survival. It does this by binding to a variety of “super-enhancers” – large regions of DNA that regulate gene expression – to promote the expression of oncogenes, which are genes that can lead to cancer development when overexpressed.
The team’s efforts show the importance of the non-canonical NF-κB pathway and its active p52 transcription factor in the reprogramming of DNA to favour cancer cell development. They have also identified a new p52 regulated non-coding RNA (ribonucleic acid) that is involved in the mechanisms of chemoresistance in multiple myeloma. With this newly acquired knowledge of the non-canonical NF-κB pathway, the p52 protein and its regulation of the non-coding genome, the team can now focus on developing nucleic acid therapeutics that can more specifically and more effectively target the cancer cell epigenome as well as the non-canonical NF-κB pathway.
To find out more about Prof Li’s research in fighting cancers, you can read about the advances in dealing with large B-cell lymphoma (DLBCL), and developments in breast cancer research.
