Acute Promyelocytic Leukemia — Weapons of Mass Differentiation

English Version

Acute myeloid leukemia (AML) involves the immortalization of immature myeloid progenitors and is a heterogeneous disease. Current clinical practice separates AML into low-, intermediate-, and high-risk categories according to cytogenetic anomalies. Among the low-risk subtypes of AML is acute promyelocytic leukemia (APL). Approximately 98% of persons with APL carry a translocation of chromosomes 15 and 17, typically resulting in the fusion between RAR{alpha} (retinoic acid receptor {alpha}), which encodes a retinoic acid receptor, and the promyelocytic leukemia (PML) protein. These persons are treated with all-trans retinoic acid in combination with chemotherapy; this treatment results in prolonged remission in more than 80% of patients. Patients who have a relapse are typically and often successfully treated with arsenic trioxide. A recent study by Nasr and colleagues1 sheds light on how these agents could control leukemia.

Cell-culture models have shown that the PML-RAR{alpha} fusion protein, as well as the less common t(11;17)-associated promyelocytic leukemia zinc finger (PLZF)-RAR{alpha} fusion protein, inhibits the differentiation of myeloid cell lines. This inhibition is due to the aberrant recruitment of transcription factors and histone-modifying enzymes to genes normally regulated by the retinoic acid receptor (Figure 1). Such genes encode transcription factors that stimulate myeloid development and regulators of the cell cycle. PML-RAR{alpha} also activates genes that stimulate self-renewal and perpetuation of the leukemia cell, including members of the Wnt and Notch signaling pathway. The abilities of the PML-RAR{alpha} oncoprotein to encourage self-renewal and to block differentiation can be dissociated. Leukemia develops in transgenic mice expressing PML-RAR{alpha} after a latent period of up to 1 year. Before then, only a very modest expansion of the myeloid compartment is noted, and PML-RAR{alpha} promyelocytes have gene-expression profiles that are almost identical to normal promyelocytes. Second and perhaps other lesions, as yet unknown, collaborate with PML-RAR{alpha} to block differentiation and stimulate the accumulation of malignant, self-renewing promyelocytes.


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