To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15(INK4B) gene.
Epigenetic silencing of downstream components of the transforming growth factor beta pathway including the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B, p27KIP1 and p21CIP1 is implicated in the pathogenesis of some hematological malignancies.
Methylation of the p15INK4b promoter never seems to occur in solid tumors but is a major gene silencing mechanism in hematological malignancies. p14ARF and p16INK4a promoter methylation often occurs in solid tumors but also in leukemias and lymphomas.
The p16INK4a and p15INK4b 5' CpG island hypermethylation has been described as one of the most frequent mechanisms leading to inactivation of these tumor suppressor genes in hematological malignancies.
The promoter region of the cyclin-dependent kinase inhibitor p15(INK4B) contains a CpG island that is hypermethylated in many hematologic malignancies.
Silencing of the cyclin-dependent kinase inhibitor gene p15INK4B by cytosine methylation of the promoter region has been associated with some types of hematological malignancy.
Since several TSGs and growth regulatory genes, including the p15INK4B gene, may be inactivated through promoter hypermethylation in hematological malignancies, modulation of the methylation status may be considered as a novel treatment modality in MDS.
In this review we address the function and possible role in tumorigenesis of the p15INK4B and p16INK4 genes and discuss their significance as prognostic markers in hematologic malignancies.