Data from Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma
Magdalena KlánováLadislav AnděraJan BražinaJan ŠvadlenkaSimona BenesovaJ. SoukupDana PrůkováDana VejmelkováRadek JakšaKarel HelmanPetra VočkováLucie LatečkováJan MolinskýBokang Calvin Lenyeletse MaswabiMd. Mahmudul AlamRoman KodetRobert PytlíkMarek TrněnýPavel Klener
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<div>Abstract<p><b>Purpose:</b> To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).</p><p><b>Experimental designs:</b> Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, <i>in vitro</i> and <i>in vivo</i> on primary cell-based murine xenograft models of DLBCL.</p><p><b>Results:</b> By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed <i>in vivo</i> using primary cell-based murine xenograft models of DLBCL.</p><p><b>Conclusions:</b> As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. <i>Clin Cancer Res; 22(5); 1138–49. ©2015 AACR</i>.</p></div>Keywords:
MCL1
Homoharringtonine
Immunoprecipitation
B-cell lymphoma
<p>Western blot analysis showing protein expression profile of key regulators of apoptosis in 18 DLBCL cell lines (12 germinal center B-cell-like (GCB) and 6 activated B-cell-like (ABC) DLBCL cell lines). *UPF4D cell line (GCB origin) was derived in our laboratory.</p>
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To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL.By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL.As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL.
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Homoharringtonine
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<div>Abstract<p><b>Purpose:</b> To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).</p><p><b>Experimental designs:</b> Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, <i>in vitro</i> and <i>in vivo</i> on primary cell-based murine xenograft models of DLBCL.</p><p><b>Results:</b> By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed <i>in vivo</i> using primary cell-based murine xenograft models of DLBCL.</p><p><b>Conclusions:</b> As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. <i>Clin Cancer Res; 22(5); 1138–49. ©2015 AACR</i>.</p></div>
MCL1
Homoharringtonine
Immunoprecipitation
B-cell lymphoma
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<div>Abstract<p><b>Purpose:</b> To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).</p><p><b>Experimental designs:</b> Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, <i>in vitro</i> and <i>in vivo</i> on primary cell-based murine xenograft models of DLBCL.</p><p><b>Results:</b> By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed <i>in vivo</i> using primary cell-based murine xenograft models of DLBCL.</p><p><b>Conclusions:</b> As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. <i>Clin Cancer Res; 22(5); 1138–49. ©2015 AACR</i>.</p></div>
MCL1
Homoharringtonine
B-cell lymphoma
Immunoprecipitation
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<p>Western blot analysis showing protein expression profile of key regulators of apoptosis in 18 DLBCL cell lines (12 germinal center B-cell-like (GCB) and 6 activated B-cell-like (ABC) DLBCL cell lines). *UPF4D cell line (GCB origin) was derived in our laboratory.</p>
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Abstract Introduction: We have previously shown that prostate cancer is primed to undergo apoptosis with BH3 mimetics targeting anti-apoptotic proteins, including BCL2, BCLXL, and MCL1 (Arai S, Balk SP et al. Clin Cancer Res 2018). We have also revealed that receptor tyrosine kinase inhibitors induced MCL1 degradation through integrated stress response and mitochondrial E3 ubiquitin ligase MARCH5 (Arai S, Balk SP et al. eLife 2020). Thus, we hypothesized that drugs targeting mitochondria might decrease MCL1 and induce apoptosis in prostate cancer. Methods: In this study, we have conducted a small-scale screening of a commercially available drug library (84 compounds) that is supposed to target mitochondria in prostate cancer cells. We have selected the top 5 drugs that could decrease prostate cancer cell growth at 1 μM levels. Results: Homoharringtonine, an FDA-approved translational inhibitor for chronic myelogenous leukemia, decreased cell growth within nM levels in multiple prostate cancer cell lines in vitro. Mechanistically, homoharringtonine rapidly reduced several proteins (MCL1, AR, AR-V7, and c-MYC) through translational inhibition and significantly induced apoptosis in prostate cancer cells in vitro. Importantly, homoharringtonine dose-dependently led to the regression of prostate cancer xenografts in vivo. Conclusions: Homoharringtonine might be a good candidate drug to treat prostate cancer. Citation Format: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Mai Kato, Yuta Maeno, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki. Homoharringtonine, a translational inhibitor, induces dramatic apoptosis in prostate cancer xenografts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B056.
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<p>Cell of origin (COO), BCL2 expression status and IC100 for ABT-199 (µM) and HHT (nM) are shown.</p>
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<p>Cell of origin (COO), BCL2 expression status and IC100 for ABT-199 (µM) and HHT (nM) are shown.</p>
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