Understanding How Stunted Genes May Lead to Acute Myeloid Leukemia

Looking at blood diseases such as leukemia, the breakdown of variations in this cancer type is daunting, but now better understood. This understanding of how cancer develops has evolved over time and until recently, it wasn't clear how the role of genes and their alterations affected cancer development and growth.  

Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have recently discovered how gene mutations keep blood stem cells from maturing, leading to the development of acute myeloid leukemia (AML). Genetic errors can create immature blood cells that overpopulate, crowd out healthy cells and spread, leading to this blood cancer type.

A mutation in the DNMT3A gene has been found in approximately 20% to 30% of cases of AML, gives normal cells “incorrect” genetic instructions that lead to cancer development and growth. In particular, they found that this gene mutation causes genes that tell cells to remain as undifferentiated stem cells. These faulty instructions lead to the creation of immature precursor cells that can become AML cells, the researchers found. This was first published in the journal Cancer Cell.

“Due to a large-scale cancer sequencing project, the DNMT3A gene is now appreciated to be one of the top three most frequently mutated genes in human acute myeloid leukemia, and yet the role of its mutation in the disease has remained far from clear,” said G. Greg Wang, PhD, a UNC Lineberger member and an assistant professor in the UNC School of Medicine Department of Biochemistry and Biophysics, in a news release.

Dr. Wang and his team found that a specific somatic mutation in DNMT3A caused AML cells to have a different pattern of chemical tags that affect how the genetic code is interpreted and how the cell develops. Researchers found that in cancerous cells with somatic mutation of DNMT3A, a set of so-called gene enhancers, the DNA sequences that code for “on” switches for other genetic regions--for several genes known as “stemness” genes--were left unchecked. For the stemness genes left unchecked, the stem cells in the blood were left with a constant “on” switch, allowing the cells to “forget” to mature.

These gene mutations alone do not drive the leukemia to develop, but it is with the combination of the RAS gene mutation when AML is born. The good news in this discovery is that may lead to better treatments for AML.

Dr. Wang and his colleagues have tested a potential treatment in cells with the DNMT3A mutation, finding that AML cells with the DNMT3A mutation were sensitive to specific drug inhibitors of DOT1L, a cellular enzyme involved in modulation of gene expression activities. Further investigation will reveal more.