Mutations in Gene Linked to Acute Myeloid Leukemia Can Drive Other Blood Disorders

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Research from the U.K.’s University of Birmingham explains how mutations in the RUNX1 gene can influence blood cell development and cause different types of cancer and other blood disorders.

The RUNX1 gene encodes a protein that guides the way hematopoietic stem cells change into adult blood cells. Mutations in this gene are found in about 14% of all acute myeloid leukemia cases, but are also found in familial platelet disorder, acute lymphoblastic leukaemia and in some cases of chronic myelogenous leukaemia.

Scientists were previously unsure why mutations in one gene seemed to be behind several different conditions, but they now think that different mutations can impact the blood from an earlier stage than previously thought.

To investigate the impact of different RUNX1 mutations more closely, Constanze Bonifer, a professor at the University’s Institute of Cancer and Genomic Sciences, and her team used a cell culture system to generate blood cells and then evaluated the impact of four different types of mutated RUNX1 protein on the blood cells.

“We found that every RUNX1 mutation changed cells in a different way and had a different impact on how genes responded,” commented study co-lead Sophie Kellaway, a researcher in the same department as Bonifer.

“What we have been able to demonstrate is that different genetic alterations in RUNX1 can send cells towards alternate paths of malignancy.”

Something else the researchers found, as described in the journal Life Science Alliance, was that some mutations had more of an immediate effect on the blood cells and on gene expression than others.

“The most important results we found came from studying mutations that run in families which predisposes their members to diseases such as familial platelet disorder and acute myeloid leukaemia,” said Bonifer.” The former is an aggressive cancer of the white blood cells, whereas familial platelet disorder impacts the ability to produce blood clots to stop bleeding. 

The team found some mutations changed the type of cell the stem cells became, whereas others had a more direct and pathogenic impact on the blood cells they were exposed to. Essentially, the RUNX1 protein has a profound effect on the formation of different types of blood cells and epigenetic programming of the DNA and mutations in this crucial gene can therefore cause a range of different blood disorders.

Bonifer and colleagues hope the information they uncovered could help to guide clinicians better in the future. Knowing how a given mutation is likely to impact the blood could help predict whether people are likely to develop cancer or less severe diseases like familial platelet disorder in the future and help them to prepare accordingly.

They plan to expand this research to blood donated by patient populations and assess whether the same findings can be seen in these samples before looking at ways to restore normal blood function.

“This detailed research shows that it’s not only a mutation that’s important in deciphering whether or not someone will develop a disease, but it’s precisely where the mutation occurs that can alter how blood cells develop and lead to disease,” said Rachel Kahn, Research Communications Manager at Blood Cancer UK, one of the funders of the research.

“Understanding more about what specific changes lead to the disease will help us to tailor treatments in the future, giving everyone the best possible chance of survival.”

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