Primed for the kill: occupying Bcl-2 to target death in acute myeloid leukaemia

Chemotherapy has been the mainstay of therapy for acute myeloid leukaemia (AML) for over five decades. Despite doses of cytarabine and anthracyclines approaching the limits of haematopoietic tolerance, half of all patients eventually relapse [1]. The situation is far worse for elderly patients, who are largely palliated because of the unfavourable risk-benefit ratio associated with intensive chemotherapy in older populations. Therapies tailored to specific sub-groups of AML have been remarkably effective, such as all-trans retinoic acid and arsenic for acute promyelocytic leukaemia, which have emerged as frontline therapies for this disease [2]. Other attempts to ?target? AML, such as with FLT3 inhibitors have been less successful, especially in the setting of chemotherapy failure [3]. Gaining insights into the molecular basis of treatment failure will be a key objective for improving therapeutic outcomes of this aggressive blood cancer. For certain targeted therapies, such as FLT3 inhibitors, clinical resistance has been linked to emergence of ?on-target? drug resistant mutations, which may be an important hurdle to the successful development of this drug class [4,5]. The biological basis for treatment failure with nontargeted therapies, such as chemotherapy, has been far more complex to decipher.