The Poison Oligonucleotide F10 Is Efficiently Taken Up By, and Highly Effective Against, Acute Lymphoblastic Leukemia While Sparing Normal Hematopoietic Cells

The development of imatinib to target the BCR-ABL kinase in chronic phase (CP) CML has changed the natural history of the disease. This success generated much enthusiasm for the approach in the more genetically complex acute lymphoblastic leukemia (ALL). Unfortunately, the durable responses seen in CP CML are not reproduced in BCR-ABL positive ALL. Indeed, all previous attempts to target a single oncogenic pathway in acute leukemias have resulted in transient responses with frequent relapse. An alternative approach is to use agents that target “final common pathways”, i.e. processes that must be accomplished to produce additional leukemia cells regardless of driving mutations. In this paradigm, agents are not judged by differential expression of a target, but by the degree of differential uptake. One pathway to exploit is the known increased uptake of oligonucleotides by ALL cells.