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Differentiation therapy of acute myeloid leukemia: past, present and future

Petrie, Kevina; Zelent, Arthura; Waxman, Samuelb

Current Opinion in Hematology: March 2009 - Volume 16 - Issue 2 - p 84–91
doi: 10.1097/MOH.0b013e3283257aee
Myeloid disease: Edited by Martin S. Tallman

Purpose of review Since the 1970s, the concept of differentiation therapy has been viewed as a promising and revolutionary approach for the treatment of acute myeloid leukemia (AML) and other cancers. However, the successful clinical application of differentiation therapy has only been realized since the late 1980s and only in one subtype of AML, acute promyelocytic leukemia (APL). The use of all-trans-retinoic acid (ATRA) and arsenic trioxide, both of which induce degradation of the progressive multifocal leukoencephalopathy/retinoic acid receptor α oncoprotein, in combination with chemotherapy is currently the accepted treatment of APL, presenting a potential paradigm for differentiation therapy in clinical oncology.

Recent findings We have begun to understand why ATRA fails to induce differentiation in AML. The underlying reasons identified thus far are associated with an inability to target the removal of leukemogenic fusion proteins, aberrant epigenetic regulation of genes involved in the ATRA signaling pathway and the presence of factors that interfere with proper retinoic acid receptor α function.

Summary Here, we examine the reasons why the exquisite sensitivity of APL to ATRA-based differentiation therapy has not been extended to other of AML subtypes. Current differentiation-based combinatorial approaches to target AML will also be analyzed. Finally, we will evaluate the potential of novel strategies, high-throughput screening, and functional genomics to uncover new differentiation-based therapies for AML.

aSection of Haemato-Oncology, Institute of Cancer Research, Sutton, UK

bDepartment of Medicine, Mount Sinai School of Medicine, New York, USA

Correspondence to Samuel Waxman, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA Tel: +1 212 241 6771; fax: +1 212 996 5787; e-mail:

© 2009 Lippincott Williams & Wilkins, Inc.