Human
myeloid leukemias provide models of maturation arrest and differentiation
therapy of
cancer. The genetic lesions of
leukemia result in a block of differentiation (maturation arrest) that allows myeloid leukemic cells to continue to proliferate and/or prevents the terminal differentiation and apoptosis seen in normal white blood cells. In
chronic myeloid leukemia, the bcr-abl (t9/22) translocation produces a fusion product that is an activated
tyrosine kinase resulting in constitutive activation cells at the myelocyte level. This activation may be inhibited by
imatinib mesylate (Gleevec, STI-571), which blocks the binding of
ATP to the activated
tyrosine kinase, prevents phosphorylation, and allows the leukemic cells to differentiate and undergo apoptosis. In
acute promyelocytic leukemia, fusion of the
retinoic acid receptor-alpha with the gene coding for promyelocytic
protein, the PML-RAR alpha (t15:17) translocation, produces a fusion product that blocks the activity of the promyelocytic
protein, which is required for formation of the granules of promyelocytes and prevents further differentiation. Retinoic
acids bind to the
retinoic acid receptor (RAR alpha) component of the fusion product, resulting in degradation of the fusion
protein by ubiquitinization. This allows normal PML to participate in granule formation and differentiation of the promyelocytes. In one common type of
acute myeloid leukemia, which results in maturation arrest at the myeloid precursor level, there is a mutation of FLT3, a transmembrane
tyrosine kinase, which results in constitutive activation of the
IL-3 receptor. This may be blocked by agents that inhibit farnesyl
transferase. In each of these examples, specific inhibition of the genetically altered activation molecules of the leukemic cells allows the leukemic cells to differentiate and die. Because
acute myeloid leukemias usually have mutation of more than one gene, combinations of specific inhibitors that act on the effects of different specific genetic lesions promises to result in more effective and permanent treatment.