Gene defect predisposes people to leukemia

AML cells

A new study suggests mutations in the GATA2 gene predispose people to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

This research began when Marshall Horwitz, MD, PhD, of the University of Washington Medical Center, came across an AML patient who had several family members with MDS, AML, and intractable mycobacteria infections. And Dr Horwitz decided to seek a genetic cause for this occurrence.

“While several genes have been discovered and linked to solid, malignant tumors . . . , so far, very few inherited mutations have been uncovered for blood cancers,” Dr Horwitz said.

In an attempt to change that, he joined with colleagues at the University of Australia in Adelaide. Together, the team studied 4 unrelated families who, over generations, had several relatives with AML. Patients’ age at disease onset ranged from early teens to early 40s, and the disease course was rapid.

Previously, scientists had linked mutations in 2 other genes—RUNX1 and CEBPA—to inherited forms of MDS and AML. Keeping this in mind, Dr Horwitz and his colleagues looked for mutations in similar genes in families who did not have the RUNX1 and CEBPA mutations and had no other explanations for developing MDS or AML.

In so doing, the researchers identified the GATA2 mutations in these families. The team also went on to identify abnormal GATA2 genes in more than 20 families.

In some families with a GATA2 mutation, the over-riding concern has been leukemia, while others suffer infections from bacteria, viruses, and fungi due to a lack of white blood cells. The researchers observed that these mutations relate to loss of function by making the gene unable to perform the molecular duties necessary to manufacture healthy white blood cells.

According to Dr Horwitz, the GATA2 mutations in DNA occur adjacent to an amino acid mutated in some patients with terminal chronic myeloid leukemia. This proximity suggests a common pathway may be critical for several types of myeloid malignancies.

Additional knowledge about how the GATA2 gene and its mutations operate may foster the development of new therapeutic agents, the researchers say. That’s why a clinical trial is currently underway to uncover specific treatment recommendations for individuals with GATA2 genetic mutations.

This research appeared September 4 in Nature Genetics.

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