DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance
© 2023 by The American Society of Hematology..
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin-really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane-associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.
| Errataetall: |
CommentIn: Blood. 2023 Sep 14;142(11):943-944. - PMID 37707876 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:142 |
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| Enthalten in: |
Blood - 142(2023), 11 vom: 14. Sept., Seite 973-988 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhou, Nan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.09.2023 Date Revised 24.03.2024 published: Print CommentIn: Blood. 2023 Sep 14;142(11):943-944. - PMID 37707876 Citation Status MEDLINE |
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| doi: |
10.1182/blood.2022018752 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357380177 |
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| 245 | 1 | 0 | |a DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance |
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| 500 | |a Date Completed 15.09.2023 | ||
| 500 | |a Date Revised 24.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Blood. 2023 Sep 14;142(11):943-944. - PMID 37707876 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 by The American Society of Hematology. | ||
| 520 | |a Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin-really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane-associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Rituximab |2 NLM | |
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| 650 | 7 | |a Cyclophosphamide |2 NLM | |
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| 650 | 7 | |a Receptor, Notch2 |2 NLM | |
| 700 | 1 | |a Choi, Jaewoo |e verfasserin |4 aut | |
| 700 | 1 | |a Grothusen, Grant |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Bang-Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Diqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Zhendong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yiman |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Qinglan |e verfasserin |4 aut | |
| 700 | 1 | |a Inamdar, Arati |e verfasserin |4 aut | |
| 700 | 1 | |a Beer, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Hsin-Yao |e verfasserin |4 aut | |
| 700 | 1 | |a Perkey, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Maillard, Ivan |e verfasserin |4 aut | |
| 700 | 1 | |a Bonasio, Roberto |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Junwei |e verfasserin |4 aut | |
| 700 | 1 | |a Ruella, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Liling |e verfasserin |4 aut | |
| 700 | 1 | |a Busino, Luca |e verfasserin |4 aut | |
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