Leukemia: stem cells, maturation arrest, and differentiation therapy

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.