Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML

In summary, our understanding of the genetics of human leukemia has provided the tools that we require to develop rationally designed targeted molecular therapies. The available evidence indicates that AML is the consequence of collaboration between at least two broad classes of mutations. Class I mutations confer a proliferative and/or survival advantage without affecting differentiation, whereas class II mutations serve primarily to impair hematopoietic differentiation. We have proof-of-principle that each of these classes of mutations can be targeted with small molecules. Examples include specific inhibition of BCR/ABL by ST1471 in treatment of CML and CML blast crisis, and induction of differentiation in promyelocytic leukemias by use of all-trans retinoic acid to override the dominant negative block in differentiation induced by the PML/RARalpha fusion proteins. The combination of continued discovery and characterization of AML disease alleles with design, development and clinical testing of targeted therapies provides real hope for improved outcome in AML, and perhaps in other hematologic malignancies and solid tumors.