Genetic mutations blunt immune defences in leukaemia-linked rare bone marrow disorder

(Press-News.org) Patients with a rare genetic bone marrow disorder which puts them at increased risk of blood cancers could benefit from a discovery that may lead to new treatments to slow or reverse the disease.

 

In a new study published in Cell Reports, scientists from the University of Birmingham and University of Warwick have found that affected blood stem cells that are produced in bone marrow produce much fewer immune cells used to fight infection. The mutation in the GATA2 gene in these blood stem cells results in impaired ability to repair ongoing damage to their DNA and puts patients at risk of developing blood cancers.  The median age for patients developing Acute Myeloid Leukaemia who have this disorder is 20.

 

Dr Rui Monteiro, Associate Professor in the Institute of Cancer and Genomic Sciences at the University of Birmingham and lead author of the paper said:

 

“GATA2 deficiency is a rare disorder, where the bone marrow fails to produce sufficient immune cells due to pathogenic mutations in the GATA2 gene.

 

“Our lab has a developed a zebrafish model of the GATA2 deficiency and we have used genomics to discover how blood stem cells affected by the mutations in the GATA2 gene produce far fewer immune cells, particularly granulocytes and macrophages. Besides blunting of the immune system, the ability to deal with DNA damage in blood stem cells is impaired, which increases the likelihood of cells acquiring further mutations that lead to blood cancers.

 

“This work has thus uncovered a potential mechanism for disease progression in the human patients and will enable further investigation on ways to block, slow down or revert the appearance of blood cancers in GATA2 deficiency patients.”

 

Lower immune cell production  

Patients who have GATA2 deficiency can present at clinics with a wide range of symptoms including recurrent viral or bacterial infections, and the new study has identified the reason why these specific immune cells are being produced in much smaller numbers in patients.

 

The Monteiro lab based at the University of Birmingham developed a zebrafish model of this disease and used single cell genomics approach to better understand how disease progression occurs in these patients.

 

Blood stem cells affected by mutations in the GATA2 gene were found to produce much less granulocytes and macrophages and are therefore less able to fight off infections. They are also less able to repair damage to their DNA, which leads to increased genome instability and higher likelihood of acquiring further mutations that in turn lead to the occurrence of blood cancers at a younger age.

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