Potential Therapeutic Target Identified in Acute Myeloid Leukemia

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Clara D. Bloomfield, MD

Clara D. Bloomfield, MD

Researchers have determined that high expression of microRNA-155 (miR-155) was associated with a poorer prognosis in patients with acute myeloid leukemia (AML) and that inhibition of a molecule that regulates the microRNA may serve as a therapeutic target for these patients.

The research was recently published online by theJournal of Clinical Oncology.

MicroRNAs are considered to be critical regulators of essential cellular processes such as differentiation, proliferation, and apoptosis. Previous research has indicated thatmiR-155is upregulated in many different types of cancer, including multiple human lymphomas and leukemias as well as solid tumors such as breast, colon, and lung cancer. In addition, microRNAs are involved in the disruption of essential cellular functions and can impact treatment and outcome in patents with AML.

Approximately 40% to 50% of adult patients with AML have cytogenetically normal (CN) disease, meaning that the chromosomes of the leukemic cells appear normal when viewed under a microscope. Therefore, molecular markers are needed to guide treatment for AML in these intermediate-risk disease patients.

To determine the role ofmiR-155in AML, 363 patients with primary CN-AML had levels of the microRNA measured in pretreatment marrow and blood. In the study, 153 patients were under age 60 and 210 were age 60 and over, and all patients were treated on Cancer and Leukemia Group B (CALGB) clinical trials.

According to multivariable analyses, patients with highmiR-155expression were approximately 50% less likely to achieve complete remission (P = .007) and had a 60% increased risk of death (P < .001). In younger patients, highmiR-155expression was associated with a lower rate of complete remission compared with low expressers (P = .03; 76% vs 90%, respectively), shorter disease-free survival (P< .001; 5-year DFS, 27% vs 55%, respectively), and overall survival (P < .001; 5-year OS, 28% vs 57%, respectively).

The researchers also found that although highmiR-155expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes responsible for mechanisms that are deregulated in patients with AML, such as apoptosis, nuclear factor-&kappa;B (NF-&kappa;B) activation, and inflammation, suggesting that the mutation plays an important role in the progression of the disease.

&ldquo;Overall, our findings indicate thatmiR-155expression is a strong and independent prognostic marker in CN-AML, and they provide clinical validation of data from preclinical models that support a crucial role ofmiR-155in leukemia,&rdquo; said Clara D. Bloomfield, MD, Distinguished University Professor and Ohio State University Cancer Scholar and Senior Advisor and one of the researchers on the study, in a statement.

Additionally, researchers noted thatmiR-155is reported to be a target of NF-&kappa;B, and so targeting the pathway might be an effective approach to treating patients with high expression of the microRNA. In an accompanying editorial, Carlo M. Croce, MD, professor and chair in the department of Molecular Virology, Immunology and Medical Genetics at Ohio State University&rsquo;s Human Cancer Genetics Program, wrote thatmiR-155overexpression should be reverted if oncologists and hematologists want to successfully treat this group of AML patients. &ldquo;Given thatmiR-155is relatively easy to measure at diagnosis, we should consider the levels ofmiR-155as a biomarker for risk stratification and guidance for treatment,&rdquo; Croce wrote.

Marcucci G, Maharry KS, Metzeler KH, et al. Clinical role of microRNAs in cytogenetically normal acute myeloid leukemia:miR-155upregulation independently identifies high-risk patients [published online ahead of print May 6, 2013].J Clin Oncol