Prognostic impact and targeting of CRM1 in acute myeloid leukemia

Kensuke Kojima, Steven M. Kornblau, Vivian Ruvolo, Archana Dilip, Seshagiri Duvvuri, R. Eric Davis, Min Zhang, Zhiqiang Wang, Kevin R. Coombes, Nianxiang Zhang, Yi Hua Qiu, Jared K. Burks, Hagop Kantarjian, Sharon Shacham, Michael Kauffman, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

175 Scopus citations

Abstract

Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects of a novel small-molecule selective inhibitor of CRM1. CRM1 protein expression was determined in 511 newly diagnosed AML patients and was correlated with mouse double minute 2 (MDM2) and p53 levels. High CRM1 expression was associated with short survival of patients and remained an adverse prognostic factor in multivariate analysis. CRM1 inhibitor KPT-185 induced mainly full-length p53 and apoptosis in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. Patient samples with p53 mutations showed low sensitivity to KPT-185. Nuclear retention of p53 induced by CRM1 inhibition synergized with increased levels of p53 induced by MDM2 inhibition in apoptosis induction. KPT-185 and Nutlin-3a, alone and in combination, induced synergistic apoptosis in patient-derived CD341/CD38 AML, but not in normal progenitor cells. Data suggest that CRM1 exerts an antiapoptotic function and is highly prognostic in AML. We propose a novel combinatorial approach for the therapy of AML, aimed at maximal activation of p53-mediated apoptosis by concomitant MDM2 and CRM1 inhibition.

Original languageEnglish
Pages (from-to)4166-4174
Number of pages9
JournalBlood
Volume121
Issue number20
DOIs
StatePublished - 16 May 2013
Externally publishedYes

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