p15Ink4b: Dual function in myelopoiesis and inactivation in myeloid disease

p15Ink4b (p15) is a cyclin-dependent kinase inhibitor (CDKI) that is known for arresting the cell cycle in early G1 phase by inhibiting the activation of cyclin dependent kinases 4 and 6. Loss of p15 expression has been associated with several cancer types but its silencing is frequent in acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS). Several mechanisms have been identified that are responsible for silencing the gene encoding p15 in myeloid disease, including gene hypermethylation, transcription factor deregulation and direct inhibition by translocation products. The effect of p15 loss during disease may be attributed to the dual role of this protein as a mediator of cell cycle arrest in late stage myeloid progenitors and as a regulator of differentiation in early common myeloid progenitors (CMP). Here we outline the mechanisms by which p15 is silenced and the functions of this CDKI in myelopoiesis as well as discuss the implications of these findings to myeloid disease.