Differentiation therapy of leukemia: 3 decades of development.
A characteristic feature of leukemia cells is a blockade of differentiation at a distinct stage in cellular maturation. In the 1970s and 1980s, studies demonstrating the capabilities of certain chemicals to induce differentiation of hematopoietic cell lines fostered the concept of treating leukemia by forcing malignant cells to undergo terminal differentiation instead of killing them through cytotoxicity. The first promising reports on this notion prompted a review article on this subject by us 25 years ago. In this review, we revisit this interesting field of study and report the progress achieved in the course of nearly 3 decades. The best proof of principle for differentiation therapy has been the treatment of acute promyelocytic leukemia with all-trans retinoic acid. Attempts to emulate this success with other nuclear hormone ligands such as vitamin D compounds and PPARgamma agonists or different classes of substances such as hematopoietic cytokines or compounds affecting the epigenetic landscape have not been successful on a broad scale. However, a multitude of studies demonstrating partial progress and improvements and, finally, the new powerful possibilities of forward and reverse engineering of differentiation pathways by manipulation of transcription factors support the continued enthusiasm for differentiation therapy of leukemia in the future.
Nowak
Daniel
D
Division of Hematology and Oncology, Cedars Sinai Medical Center, University of California Los Angeles (UCLA) School of Medicine, CA 90048, USA. daniel.nowak@cshs.org
Stewart
Daphne
D
Koeffler
H Phillip
HP
D000970:Antineoplastic Agents / Q000266:history / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000266:history / Q000378:metabolism; D009363:Neoplasm Proteins / Q000819:agonists / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D014157:Transcription Factors