Tumor suppressor genes in normal and malignant hematopoiesis.

Over the last decade, a growing number of tumor suppressor genes have been discovered to play a role in tumorigenesis. Mutations of p53 have been found in hematological malignant diseases, but the frequency of these alterations is much lower than in solid tumors. These mutations occur especially as hematopoietic abnormalities become more malignant such as going from the chronic phase to the blast crisis of chronic myeloid leukemia. A broad spectrum of tumor suppressor gene alterations do occur in hematological malignancies, especially structural alterations of p15(INK4A), p15(INK4B) and p14(ARF) in acute lymphoblastic leukemia as well as methylation of these genes in several myeloproliferative disorders. Tumor suppressor genes are altered via different mechanisms, including deletions and point mutations, which may result in an inactive or dominant negative protein. Methylation of the promoter of the tumor suppressor gene can blunt its expression. Chimeric proteins formed by chromosomal translocations (i.e. AML1-ETO, PML-RARalpha, PLZF-RARalpha) can produce a dominant negative transcription factor that can decrease expression of tumor suppressor genes. This review provides an overview of the current knowledge about the involvement of tumor suppressor genes in hematopoietic malignancies including those involved in cell cycle control, apoptosis and transcriptional control.