Related Experiment Video
Updated: May 21, 2026
Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia
Parvathi Ranganathan1, Xueyan Yu, Caroline Na
1Division of Hematology, Department of Medicine, The Ohio State University, Columbus 43210, USA.
Abstract:
Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (e.g., p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRM1-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500 nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild-type cell lines was observed. Finally, using the FLT3-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P < .01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.
Insights
Selective inhibitors of nuclear export (SINE) targeting Chromosome maintenance protein 1 (CRM1) show potent antileukemic activity. These novel KPT-SINE compounds effectively inhibit acute myeloid leukemia cell growth and prolong survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor crucial for tumor suppressor protein transport, often dysregulated in cancer.
- Overactive CRM1-mediated nuclear export contributes to cancer progression by reducing tumor suppressor function.
- Selective inhibitors of nuclear export (SINE) represent a novel therapeutic strategy to restore tumor suppressor activity.
Purpose of the Study:
- To investigate the antileukemic activity of KPT-SINE compounds (KPT-185 and KPT-276) in acute myeloid leukemia (AML).
- To evaluate the efficacy of KPT-SINE in both in vitro and in vivo AML models.
Main Methods:
- In vitro studies using AML cell lines and patient blasts to assess antiproliferative, apoptotic, cell-cycle arrest, and differentiation effects.
- In vivo studies using a murine xenograft model of acute myeloid leukemia (MV4-11) to evaluate survival benefits.
- Analysis of FLT3 oncogene expression following KPT treatment.
Main Results:
- KPT-185 demonstrated potent antiproliferative effects (IC50 100-500 nM), induced apoptosis, cell-cycle arrest, and myeloid differentiation in AML cells.
- Significant down-regulation of the FLT3 oncogene was observed in both FLT3-ITD and wild-type AML cell lines after KPT treatment.
- Oral administration of KPT-276 significantly prolonged survival in a murine AML xenograft model (P < .01).
Conclusions:
- KPT-SINE compounds exhibit potent in vitro and in vivo antileukemic activity against acute myeloid leukemia.
- The preclinical efficacy of KPT-SINE supports their further investigation in clinical trials for AML treatment.
