Roles of p15Ink4b and p16Ink4a in myeloid differentiation and RUNX1-ETO-associated acute myeloid leukemia

Academic Article

Abstract

  • Inactivation of p15Ink4b 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 p15Ink4b 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, p15Ink4b or p16Ink4a knockout bone marrow. Analysis of lethally irradiated recipient mice reconstituted with RUNX1-ETO-expressing cells showed that neither p15Ink4b or p16Ink4a loss significantly accelerated disease progression over the time period of one year post-transplantation. Loss of p15Ink4b 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 p15Ink4b loss must be accompanied by additional oncogenic changes for RUNX1-ETO-associated AML to develop. © 2007 Elsevier Ltd. All rights reserved.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 16220643
  • Author List

  • Ko RM; Kim HG; Wolff L; Klug CA
  • Start Page

  • 1101
  • End Page

  • 1111
  • Volume

  • 32
  • Issue

  • 7