Most
acute promyelocytic leukemia (APL) cases have t(15;17)(q22;q21)
chromosomal translocation and
PML-RARalpha chimeric gene which blocks granulocytic differentiation. The introduction of
all-trans-retinoic acid (ATRA) and
arsenic compounds, especially
arsenic trioxide (
As(2)O(3)), has provided good models to study not only differentiation and/or apoptosis
therapy but also molecular target-based
cancer treatment. In vivo and in vitro investigations have shown that both agents are able to induce differentiation of APL cells: ATRA tends to induce terminal differentiation, while low-dose
As(2)O(3) can induce partial differentiation. Significant progress has been made in understanding the molecular mechanisms of APL pathogenesis and differentiation
therapy. Pharmacological concentrations (0.1 approximately 1 microM) of ATRA derepresses transcription by releasing CoR from, and recruiting
CoA to
PML-RARalpha, whereas
As(2)O(3) triggers a rapid degradation of
PML-RARalpha. In fact, the two drugs act on the same
oncoprotein through targeting different moieties and in distinct ways and thereby abrogate its dominant-negative effects on regulatory pathways necessary for granulocytic differentiation. As to apoptosis, it is clear that high-dose
As(2)O(3) can induce mitochondria-mediated cell death pathway in a
thiol-dependent manner, while the mechanism of ATRA-induced apoptosis needs further elucidation. Transcriptomic and proteomic analysis are also expected to find new molecular targets. It is the hope that what we have learnt from APL will benefit further developments of anti-
leukemia therapy.