Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing.

The t(15;17) translocation that results in the PML/RARA fusion is the disease-defining lesion in nearly all cases of acute promyelocytic leukemia (APL).1 Despite the importance of the PML/RARA fusion for the pathogenesis of APL, it is most likely not sufficient to cause leukemia. The long latency, incomplete penetrance and additional cytogenetic changes accompanying the onset and progression of the disease in the murine APL models strongly suggest that additional mutations are required for the development of APL.2 In newly diagnosed patients with APL, approximately 40% have leukemic cells with secondary abnormalities.3 Collaborating mutations affecting the FLT3 receptor tyrosine kinase are found in about 20–30% of APL patients and a synergism between FLT3 mutations and PML/RARA was also observed in murine APL models.4