Constitutive gene expression and restoration of the normal phenotype in malignant cells: a model for the origin and evolution of leukemia.

The change from normal to malignant cells involves a sequence of changes including specific chromosome changes. After this sequence, some leukemias can still be induced to revert with a high frequency from a malignant to a non-malignant phenotype. Results obtained from the analysis of regulation of growth and differentiation in normal and leukemic myeloid cells, restoration of the normal phenotype by induction of normal differentiation in myeloid leukemia, and the blocks in differentiation defective leukemic cell mutants have been used to propose a general model for the origin and evolution of leukemia. The model states that leukemia originates by changing specific pathways of gene expression required for growth from inducible to constitutive, in cells that can still be induced to differentiate normally by the physiological inducer of differentiation. The malignant, unlike the normal cells, then no longer require the physiological inducer for growth. This changes the requirements for growth and uncouples growth from differentiation. Constitutive expression of other specific pathways of gene expression can uncouple other controls, which then causes blocks in differentiation and the further evolution of leukemia. The existence of specific constitutive pathways of gene expression that uncouple controls in malignant cells, can also explain the origin and evolution of other types of malignancies.