Researchers Find Genetic Network Responsible For Aggressive AML
By C. Rajan, contributing writer
Researchers from the Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children's Hospital Medical Center have identified a genetic network responsible for an aggressive form of Acute Myeloid Leukemia (AML) and its precursor disease Myelodysplastic Syndrome (MDS). This new finding could hold the keys to the development of a possible therapeutic strategy for this untreatable form of leukemia.
The specific forms of AML and MDS investigated in this study had certain deletions on the arm of a specific chromosome in blood cells (del(5q)). Patients with the more aggressive forms of leukemia and MDS have more of these mutations, and a higher percentage of bone marrow blasts (immature blood cells).
Dr. Daniel Starczynowski, the study's lead investigator and a researcher in the Experimental Hematology and Cancer Biology division of the CBDI at Cincinnati Children's said, "Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations," Dr. Starczynowski said. "These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities."
Acute myeloid leukaemia (AML) is a type of cancer that affects the blood and bone marrow. According to the American Cancer Society, there will be an estimated 18,800 new cases of AML in 2014, with over 10,000 deaths due to AML. This type of leukemia is characterized by an overproduction of immature white blood cells, called myeloblasts, which are incapable of performing the important tasks of normal while blood cells. One of the most important factors in determining the prognosis for patients with this condition is the genetic make-up of the leukemic cells.
In the present study, the researchers used human AML/MDS cells and mouse models of del(5q) AML/MDS, and found that reduced expression of a certain gene in blood cells (miR-146a) activated a molecular signaling network involving a protein called p62 – a critical regulator of cell metabolism, cellular remodeling, and certain cancers. When the miR-146a gene was deleted, it resulted in overexpression of p62, which in turn fueled the survival and aggressive growth of the leukemic cells.
As a possible treatment strategy, the researchers tried inhibiting/knocking down p62 in mouse models of leukemia and in human cells, and found that it prevented the expansion of leukemic cells in mouse models and reduced the number of leukemia cell colonies by 80 percent in human AML/MDS cells.
Dr. Starczynowski cautions that the study is still in preliminary stages and further research is needed to verify the findings and understand the molecular processes involved in order to develop new therapies. The results of the study were published online in the journal Cell Reports on Sept 4.