July 2015, Special ASCO Edition

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Activating KIR Genes Implicated in Development of MDS

Genetics

Evidence from a case-control study implicates the number of activating killer-cell immunoglobulin-like receptor (KIR) genes in the risk of developing myelodysplastic syndrome (MDS) as well as being able to distinguish between high-risk and low-risk MDS once the disease is present.

Specifically, patients with high-risk MDS had significantly lower numbers of activating KIR genes compared with patients with low-risk MDS (P = .009) and compared with healthy controls (P = .00001). Patients with low-risk MDS also had significantly lower numbers of activating KIR genes compared with controls (P = .04).

Moreover, the investigators found that the inheritance of each additional activating KIR gene had a protective effect against development of high-risk MDS (P <.001).

“This study provides novel insights concerning the pathogenesis of MDS in adults. These results suggest that inheritance of a higher number of activating KIR genes is protective against MDS, and that once the disease develops, harboring a lower number of KIR genes is associated with higher-risk disease,” said lead author May Deher, MD, The University of Texas MD Anderson Cancer Center, Houston.

MDS is not a single disorder, but rather a spectrum of clonal hematopoietic disorders affecting the myeloid lineage. MDS can be risk-stratified using the International Prognostic Scoring System (IPSS); outcomes are related to risk category.

The major concern with MDS is its potential to evolve to acute myeloid leukemia (AML), which is difficult to treat and occurs in about 20% of patients with MDS. Evidence suggests that genetic factors play a role in conferring susceptibility/resistance to MDS, Deher explained.

KIR genes expressed in natural killer [NK] cells are an area of particular interest in this regard,” she told listeners.

NK cells comprise about 5% to 15% of peripheral blood lymphocytes. They are important in tumor surveillance and infectious disease control and can be the first line of defense against tumors.

The study population included 180 MDS patients; of these, 120 were low risk, and 60 were high risk. MDS patients were compared with 117 healthy donor controls. The age distribution was similar between the MDS patients and controls; more than 80% were older than 60 years.

Transformation to AML occurred in 12% of the low-risk patients versus 20% in the high-risk group.

DNA samples were collected in both cases and controls and analyzed for activating KIR genes using polymerase chain reaction.

No independent survival benefit was associated with increased numbers of activating KIR genes.

“Our study has implications for the development of new immunotherapies using NK cells with the potential of controlling the disease and preventing the progression to high-risk disease and eventually to AML,” Deher stated.

This abstract won the Merit Award at ASCO 2015.

“The novel and major finding of this explorative study is that NK genotype may be associated with MDS risk,” said formal discussant Wendy Stock, MD, University of Chicago, IL.

“We do have good markers for MDS, and the IPSS and molecular heterogeneity will help us refine our prognostic ability,” she continued.

“This work is interesting and preliminary. We can’t assume the number of KIR genes is associated with prognosis. The findings need to be confirmed in a larger cohort of MDS patients. We need to determine if activating KIR genes do provide immune surveillance and protection for the myeloid progenitor cells,” Stock commented.

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