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Picture: In a genetic mouse model, the biallelic DDX41 mutation causes the death of blood progenitor cells, leading to bone marrow failure and spleen atrophy
.
Source: Cincinnati Children
In the United States, as many as 187,000 people are dealing with myelodysplastic syndrome (MDS), a disease that destroys the bone marrow's ability to produce healthy blood cells
.
In most cases, MDS is caused by mutations in blood stem cells during a person's lifetime
.
These patients develop anemia, fatigue, and other complications, and the typical diagnosis age of MDS is 70 years and older
In 2016, other scientists documented that people with this inherited form of adult MDS have common mutations in the DDX41 gene, but it is not clear what role these mutations play
.
Now, a study led by experts from the Cincinnati Institute of Childhood Cancer and Blood Diseases, published in "Cell Stem Cells" on September 1, 2021, explains its importance
Their discovery is based on a lot of work to develop a more accurate mouse model of human MDS, which is caused by the DDX41 mutation
.
An important aspect of this disease seems to depend on the cell acquiring additional mutations in another copy of its DDX41 gene, resulting in blood stem cells with two DDX41 mutations
The research team concluded that these relatively rare cells in the patient’s bone marrow may indirectly affect the rest of the bone marrow and cause abnormal blood production
.
In this way, this small cell population may become a driving factor for MDS
Dr.
Daniel Starczynowski, senior author of the study, said: "Basically, these rare cells help create a contaminated bone marrow environment, which in turn allows other stem cells with mds-related gene mutations to thrive
.
" "Without these With the presence of trigger cells, the bone marrow may produce blood cells as normal as the patient’s life
Although the focus of this study is MDS, similar types of crosstalk between cells with different combinations of mutations may play a role in other diseases
.
Starczynowski said: "As far as we know, this is the first evidence that inherited or newborn MDS can be mediated by disease-modifying small clones in the bone marrow
.
"
What is MDS?
Myelodysplastic syndrome includes a group of diseases that impair bone marrow function
.
About 75% of cases occur in people over 60 years old, but the disease also affects children and young people
Sometimes MDS is a side effect of cancer radiotherapy or chemotherapy
.
Some cases may be related to toxic environmental exposure or rare genetic diseases such as Fanconi anemia
Patients with advanced MDS require bone marrow transplantation
.
The average survival rate without bone marrow transplantation is about 6 years, but some patients may die of bone marrow failure within a few months
.
Detect silent trigger
Starczynowski and his colleagues have been studying MDS for many years
.
After learning that the genetic mutation of the DDX41 gene is related to MDS from other studies in this field, the team began to develop a mouse model, hoping to learn more about the genetic mutation
.
"Cells with this additional DDX41 mutation do not make up the bulk of the bone marrow
.
In fact, it is difficult to grow cells with this combination of mutations," said Dr.
Tim Cullen , the first author of the study
.
"Once we realized that these cells are rare in the bone marrow of patients, we thought that the crosstalk between these cells and other cells in the bone marrow might play a role in the pathogenesis of the disease
.
"
Experiments in mice have shown that blood stem cells that have mutations in both copies of the DDX41 gene have defects in their mechanism for making new proteins (called ribosomes)
.
This prevents the proliferation of stem cells and the formation of a normal number of new blood cells
.
Since these cells cannot multiply efficiently, they do not cause bone marrow failure by themselves, but they can affect other cells in the bone marrow, leading to ineffective blood cell production
.
This process may help explain why these patients with MDS can feel completely normal before the onset of the disease suddenly, until later in adulthood
.
Next step
The research team plans to conduct further studies to determine whether targeting cells with slight clonal DDX41 mutations will alter the progression of MDS in the mouse model, and if successful, may lead to potential human drug development
.
This discovery may also serve as a springboard for other studies to find similar crosstalk between potentially overlooked small cell populations and their richer followers
.
