Skip to main content
main-content

01.12.2019 | Rapid communication | Ausgabe 1/2019 Open Access

Journal of Hematology & Oncology 1/2019

Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2019
Autoren:
Yuanhui Liu, Nancy G. Azizian, Yaling Dou, Lan V. Pham, Yulin Li
Wichtige Hinweise

Supplementary information

Supplementary information accompanies this paper at https://​doi.​org/​10.​1186/​s13045-019-0803-9.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abstract

Double-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes. DHLs carry genomic abnormalities in MYC, BCL2, and/or BCL6 oncogenes. Due to the simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag als Mediziner

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

e.Med Innere Medizin

Kombi-Abonnement

Mit e.Med Innere Medizin erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes Innere Medizin, den Premium-Inhalten der internistischen Fachzeitschriften, inklusive einer gedruckten internistischen Zeitschrift Ihrer Wahl.

Zusatzmaterial
Additional file 1: Fig S1. (A) Western blot analysis of MYC, MCL1, XPO1, and PARP/Caspase 3 cleavage. A panel of DHL cell lines was treated with 1 μM KPT8602 for 24 h. (B) Western blot analysis of MYC and PARP/Caspase 3 cleavage upon XPO1 inhibition in three DHL cell lines. (C) Western blot analysis of MYC and PARP/Caspase 3 cleavage upon treatment with different concentrations of XPO1 inhibitors for 24 hours. Fig S2. (A) Total mRNA and (B) nuclear to cytoplasmic ratios of BCL2, BCL6 and β-tubulin in DHL6 treated with 1 μM KPT8602. All mRNA levels were normalized to GAPDH. (C) Quantification of nuclear and cytoplasmic Neat1 mRNA levels by real-time PCR. (D) Analysis of nuclear and cytoplasmic GAPDH (cytoplasmic marker) and Lamin B1 (nuclear marker) by Western Blot. (E) Representative DHL cells were treated with 1 μM KPT8602 and/or 10 nM Carfilzomib for 24 hours. Fig S3. (A) IC50 values for ABT199 in a panel of DHL cell lines. (B) IC50 values for KPT8602 in a panel of DHL cell lines. (C) Cell viability in DHL cells treated with KPT8602 and ABT199 for 72 hours. The IC50 values for KPT8602 were calculated in the presence of different concentrations of co-administered ABT199. (D) Cell morphology of DHL cells treated with KPT8602 (100 nM) and ABT199 (40 nM for DHL4/DHL6, and 20 nM for Toledo) for 48 hours. Fig S4. Western blot analysis of MCL1, BCL-XL, and BIM proteins in DHL4 (A), DHL6 (B), and Toledo (C) cells. The drug treatment is the same as Fig 3b-d. Fig S5. Quantification of BLI signals from the crania of the tumor bearing animals following drug treatment. BLI signal data were presented as mean + standard error of mean. Two-tailed t test. * Control vs ABT199, P = 0.02; ** Control vs KPT8602, P = 0.01; *** Control vs Combination, P = 0.0008.
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2019

Journal of Hematology & Oncology 1/2019 Zur Ausgabe

Neu im Fachgebiet Onkologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise