Novel genomic determinants of apoptotic defects in acute lymphoblastic leukemia

The treatment of pediatric acute leukemia has greatly improved over the past 4 decades, resulting in long-term disease-free survival of approximately 80% for ALL1-3 and 60% for AML.4 Despite this progress, a considerable number of children ultimately relapse with a disease that is highly refractory to further treatment. A high proportion of the contemporary treatment failures can be contributed to cellular drug resistance. However, relatively little is known about the causes of cellular drug resistance in childhood acute leukemia. In the last years it has become clear that most, if not all, chemotherapeutic agents ultimately induce programmed cell death or apoptosis in their target cells.5 Defects in the apoptosis route allow genetically instable cells to survive and are thought of as one of the major driving forces behind leukemogenesis.6,7 These observations led to the hypothesis that aberrations in the apoptosis pathway contribute to cellular drug resistance in children with acute leukemia. Therefore, a thorough knowledge of the aberrations in the apoptosis route is critical for understanding the causes of treatment failure and for a rational approach to drug design and therapy.