Differentiation therapy of acute myeloid leukemia: past, present and future.
OBJECTIVE
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 alpha oncoprotein, in combination with chemotherapy is currently the accepted treatment of APL, presenting a potential paradigm for differentiation therapy in clinical oncology.


RESULTS
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 alpha function.


CONCLUSIONS
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.
Petrie
Kevin
K
Institute of Cancer Research, Sutton, UK.
Zelent
Arthur
A
Waxman
Samuel
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000627:therapeutic use*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012680:Sensitivity and Specificity; D014212:Tretinoin / Q000378:metabolism / Q000627:therapeutic use*
D001152:Arsenicals; D010087:Oxides; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000077237:Arsenic Trioxide