We have new insights into potential therapeutic approaches to AML based on a thorough and comprehensive effort to identify disease alleles that are causally implicated in disease pathogenesis. These include strategies that target the block in differentiation, with ATRA treatment in APL as the paradigm for this approach. In addition, inhibitors of proliferative and/ or survival mutations such as FLT3 may also prove therapeutically useful. Future directions include the identification of additional proliferative and survival mutations that may be targets for small-molecule inhibitions, and screens for compounds that override the block in differentiation. Eventually, it may be possible to use combinations of molecularly targeted therapies, such as FLT3 inhibitors plus ATRA, in selected clinical contexts to improve outcome and reduce toxicity.

To the extent that these therapies are successful, we can anticipate the development of resistance to single agents, such as FLT3 inhibitors and ATRA. ATRA resistance develops in most APL patients, which is one reason why current therapy always includes a combination of ATRA with conventional induction chemotherapy. Imatinib resistance is well described, particularly in chronic myelogenous leukemia blast crisis patients, and we should anticipate this problem and begin to develop strategies to circumvent or prevent resistance to FLT3 inhibitors. It may be possible to address the problem of resistance to small-molecule kinase inhibitors using alternative inhibitors with different chemical structures.

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