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- Title
KPT-330 inhibitor of CRM1 ( XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia.
- Authors
Etchin, Julia; Sanda, Takaomi; Mansour, Marc R.; Kentsis, Alex; Montero, Joan; Le, Bonnie T.; Christie, Amanda L.; McCauley, Dilara; Rodig, Scott J.; Kauffman, Michael; Shacham, Sharon; Stone, Richard; Letai, Anthony; Kung, Andrew L.; Thomas Look, A.
- Abstract
This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 ( CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia ( T- ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T- ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2 A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T- ALL and acute myeloid leukaemia ( AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T- ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T- ALL and AML.
- Subjects
LYMPHOBLASTIC leukemia; ACUTE myeloid leukemia; BONE marrow diseases; T cells; LEUKEMIA
- Publication
British Journal of Haematology, 2013, Vol 161, Issue 1, p117
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.12231