1. Academic Validation
  2. DLBCL associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemo-resistance

DLBCL associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemo-resistance

  • Blood. 2023 May 26;blood.2022018752. doi: 10.1182/blood.2022018752.
Nan Zhou 1 Jaewoo Choi 2 Grant Peter Grothusen 1 Bang-Jin Kim 2 Diqiu Ren 1 Zhendong Cao 1 Qinglan Li 1 Yiman Liu 1 Arati Inamdar 1 Thomas Beer 3 Hsin-Yao Tang 3 Eric Perkey 4 Ivan Maillard 1 Roberto Bonasio 1 Junwei Shi 1 Marco Ruella 1 Liling Wan 1 Luca Busino 1
Affiliations

Affiliations

  • 1 University of Pennsylvania, Philadelphia, Pennsylvania, United States.
  • 2 University of Pennsylvania, United States.
  • 3 The Wistar Institute, Philadelphia, Pennsylvania, United States.
  • 4 University of Michigan, Ann Arbor, Michigan, United States.
Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. Up to 40% of DLBCL patients display refractory disease or relapse after standard chemotherapy treatment (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), leading to significant morbidity and mortality. The molecular mechanisms of chemo-resistance in DLBCL remain incompletely understood. Utilizing a CULLIN-RING ligases based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin Ligase KLHL6 promotes DLBCL chemo-resistance. Furthermore, proteomic approaches identified 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 g-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL death. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.

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