Apoptosis-stimulating proteins of p53 (ASPPs) are a family of proteins that modulate
key tumor suppressor pathways via direct interaction with p53. Deregulation of these
proteins promotes cancer development and impairs sensitivity to systemic (chemo)therapy
and radiation. In this study, we describe that the inhibitor of ASPP (iASPP) is frequently
highly expressed in acute myeloid leukemia (AML) and that overexpression correlates
with a poor clinical outcome. Four independent patient cohorts comprising about 1500
patient samples were analysed and consistently confirm an association of high iASPP
expression with unfavourable clinical characteristics and shorter survival. Notably,
the predictive role of iASPP is independent of, and adds information to, the European
LeukemiaNET (ELN) risk classification. iASPP -interference cell models were developed
to investigate the underlying functional aspects of iASPP in AML biology. Attenuation
of iASPP expression resulted in reduced proliferation rates of leukemic blasts and
rendered cells more susceptible towards induction of apoptosis in response to cytotoxic
therapy. In line, independent NSG xenograft mouse experiments demonstrate that attenuation
of iASPP results in a significant delay of disease onset and tumor burden and this
translates to longer overall survival of mice. In conclusion, deregulation of iASPP
has direct functional consequences in AML. Determination of iASPP expression levels
provides valuable additional information as a predictive marker in AML and may guide
treatment decisions.
