In vitro and in vivo characterization of new molecular targets for the treatment of Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML), accounting for around 10–15% of cases. Ninety percent of APL patients have the reciprocal and balanced chromosomal translocation t(15;17), which determines the heterozygous expression of the PML-RARα oncoprotein fusion protein. The expression of this oncoprotein is necessary and sufficient for the onset of the disease as it acts through a dominant-negative mechanism with respect to wild-type PML and RARα proteins. PML-RARα specifically causes the maturation of myeloid progenitors (promyelocytes) to arrest by interfering with the gene transcription regulation necessary for the differentiation of leukemic blasts, as it inhibits the transcriptional function of the retinoic acid receptor α (RARα). Furthermore, PML-RARα negatively interferes with the polymerization of PML proteins, resulting in the impaired formation of PML nuclear bodies (PML-NBs). An effective therapeutic approach for treating APL involves administering