Roles of p15 Ink4b and p16 Ink4a in myeloid differentiation and RUNX1-ETO-associated acute myeloid leukemia

Abstract

Inactivation of p15 Ink4b expression by promoter hypermethylation occurs in up to 80% of acute myeloid leukemia (AML) cases and is particularly common in the FAB-M2 subtype of AML, which is characterized by the presence of the RUNX1-ETO translocation in 40% of cases. To establish whether the loss of p15 Ink4b contributes to AML progression in association with RUNX1-ETO, we have expressed the RUNX1-ETO fusion protein from a retroviral vector in hematopoietic progenitor cells isolated from wild-type, p15 Ink4b or p16 Ink4a knockout bone marrow. Analysis of lethally irradiated recipient mice reconstituted with RUNX1-ETO-expressing cells showed that neither p15 Ink4b or p16 Ink4a loss significantly accelerated disease progression over the time period of one year post-transplantation. Loss of p15 Ink4b alone resulted in increased myeloid progenitor cell frequencies in bone marrow by 10-month post-transplant and a 19-fold increase in the frequency of Lin −c-Kit +Sca-1 + (LKS) cells that was not associated with expansion of long-term reconstituting HSC. These results strongly suggest that p15 Ink4b loss must be accompanied by additional oncogenic changes for RUNX1-ETO-associated AML to develop.