Mutations Affect Acute Myeloid Leukemia Treatment Outcomes

November 22, 2010
Mutations Affect Acute Myeloid Leukemia Treatment Outcomes

Researchers have discovered mutations in a particular gene that affects the treatment prognosis for some patients with acute myeloid leukemia (AML), an aggressive blood cancer that kills 9,000 Americans annually. The finding may lead to more effective treatments for patients who carry the mutations.



Image of Human cells with acute myeloid leukemia.
Human cells with acute myeloid leukemia. Image by Dr. Lance Liotta laboratory, courtesy of NCI.

AML gets harder to treat as patients get older, and the 5-year rate of survival is only about 20%. Certain laboratory tests on cancer cells can help predict treatment success. Chemotherapy is the standard treatment for patients found to have an intermediate risk profile. However, the genetic alterations that affect these outcomes are largely unknown.

A research team led by Dr. Timothy Ley at the Washington University School of Medicine set out to investigate how genetic changes affect treatment outcomes. Their work was partly supported by NIH's National Human Genome Research Institute (NHGRI), National Cancer Institute (NCI) and National Center for Research Resources (NCRR).

The researchers began by sequencing all the genes in an AML patient. As reported in the November 11, 2010, online issue of the New England Journal of Medicine, they discovered mutations in a gene called DNMT3A. DNMT3A is a DNA methyltransferase—an enzyme that adds methyl groups to DNA. Methylation is a common modification that affects gene expression—and that has long been thought to contribute to cancer.

The researchers next looked at DNMT3A in nearly 300 other AML patients. Overall, 21% carried the mutations. Among patients at intermediate risk for treatment failure, 56 of 166 (34%) had the mutations. In contrast, none of the 79 patients with a favorable risk profile carried them.

The researchers found that the average survival time for patients with the DNMT3A mutations was only a year, compared to 3.5 years for patients without them. "We have not had a reliable way to predict which of these patients will respond to the standard treatment," Ley says. "In the cases we studied, mutations in the DNMT3A gene trump everything else we've found so far to predict adverse outcomes in intermediate-risk AML."

These findings may help guide future treatment strategies for patients with AML. More aggressive treatments could help those with the DNMT3A mutations live longer. The researchers saw an increase in survival in patients who received bone marrow transplants rather than chemotherapy alone. However, the sample size was small, so more work will be needed to determine the best treatment approach for these patients.

The research team has donated nearly 200 AML samples for comprehensive genomic analysis to an NIH program called The Cancer Genome Atlas (TCGA). The TCGA strategy takes cancer cells from a patient and compares the whole set of genes in those cells to the genes in normal cells from the same patient. TCGA scientists plan to analyze up to 500 patient samples of tumor and normal cells from 20 major types of cancer over the next 5 years. These analyses will reveal which genes are mutated in the cancer cells and potentially yield insights into what is causing them to grow uncontrollably.

Related Links:

* Leukemia:
http://www.cancer.gov/cancertopics/types/leukemia
* The Cancer Genome Atlas:
http://cancergenome.nih.gov/


Mutations Affect Acute Myeloid Leukemia Treatment Outcomes