title: Prognostic impact and targeting of CRM1 in acute myeloid leukemia.
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 CD34(+)/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.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. kkojima@mdanderson.org
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.forename: Archana
authors.initials: A
authors.lastname: Dilip
authors.forename: Seshagiri
authors.initials: S
authors.lastname: Duvvuri
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.forename: Jared K
authors.initials: JK
authors.lastname: Burks
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000179:Acrylates / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D058990:Molecular Targeted Therapy; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D014230:Triazoles / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020298:U937 Cells; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C576639:KPT-185; C495901:TP53 protein, human
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