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An erythroid differentiation signature predicts response to lenalidomide in Myelodysplastic Syndrome

Publication TypeJournal Article
Year of Publication2008
AuthorsBenjamin L. Ebert, Naomi Galili, PTJBRMJPCL-ARS, Raza, A
Keywordserythroid differentiation, hematopoietic disorder, lenalidomide, Myelodysplastic Syndrome (MDS), revlimid

Background: Lenalidomide is an effective new agent for the treatment of patients with Myelodysplastic Syndrome (MDS), an acquired hematopoietic disorder characterized by ineffective blood cell production and a predisposition to the development of leukemia. Patients with an interstitial deletion of chromosome 5q have a high rate of response to lenalidomide, but most MDS patients lack this deletion. Approximately 25% of patients without 5q deletions also benefit from lenalidomide therapy, but response in these patients cannot be predicted by any currently available diagnostic assays. A method to predict lenalidomide response is therefore needed in order to identify patients most likely to respond, thereby avoiding unnecessary toxicity in patients unlikely to benefit from treatment. Methods and Findings: Using gene expression profiling, we identified a molecular signature that predicts lenalidomide response. The signature was defined in a set of pre-treatment bone marrow aspirates from MDS patients without 5q deletions, and validated in an independent set of samples. The response signature was comprised of a cohesive set of erythroid-specific genes with decreased expression in responders, suggesting that a defect in erythroid differentiation underlies lenalidomide response. Consistent with this observation, treatment with lenalidomide promoted erythroid differentiation of primary hematopoietic progenitor cells grown in vitro. Conclusions: These studies indicate that lenalidomide-responsive patients have a defect in erythroid differentiation, and suggest a strategy for a clinical test to predict patients most likely to respond to the drug. The experiments further suggest that the efficacy of lenalidomide, whose mechanism of action in MDS is unknown, may be due to its ability to induce erythroid differentiation.