Note: This review is based upon a presentation at the 2014 American Society of Hematology (ASH) Annual Meeting, December 6 - 9 in San Francisco, CA.The full abstract may be reviewed on the ASH Annual Meeting Web site.
Neal S. Young, M.D.; Bogdan Dumitriu, M.D.; and Seishi Ogawa, M.D., Ph.D.
SCI-21: Acquired Aplastic Anemia: New Genetics, New Genomics
T lymphocytes are white blood cells that help protect the body from infection. In aplastic anemia, T lymphocytes destroy both immature blood cells and cells that form blood cells. Treatments that suppress the immune system (immunosuppressive therapy, IST) are effective in most patients. Adding eltrombopag (Promacta®) to IST increases response rates. When used alone, eltrombopag can also benefit patients who don’t respond to IST.
Mutations in the TERT and TERC genes, which help maintain telomeres (ends of chromosomes), play an important role in aplastic anemia. Telomeres are usually short in people with aplastic anemia, almost always because of mutations in TERT and TERC.
A study found acquired (non-inherited) mutations in about one-third of almost 300 patients with aplastic anemia patients treated with IST at the National Institutes of Health. The PIGA gene was the most commonly abnormal gene, followed by BCOR1, DNMT3A, and ASXL1. Mutations in certain combinations of these genes were associated with shorter survival and a greater risk of progression to MDS and acute myeloid leukemia. In contrast, patients with mutations in BCOR and PIGA tended to survive longer.
The authors examined patients whose aplastic anemia progressed to monosomy 7 (meaning that they had only one copy, instead of the usual two copies, of chromosome 7) and who had shortages of all three major types of blood cells and/or early leukemia. Only two patients had mutations in DNMT3A and ASXL1 and another had a RUNX1 mutation. Telomeres were very short in all of the patients with monosomy 7.
The progression of bone marrow failure to a bone marrow cancer involves the loss of one of two alleles (copies) of certain genes and changes in or losses of certain chromosomes inside bone marrow that is not working properly. The failed bone marrow might allow defective cells to grow more quickly than healthy cells. Ideally, doctors should be able to predict and treat progression from bone marrow failure to cancer.