Blockage of BCL-XL overcomes venetoclax resistance across BCL2+lymphoid malignancies irrespective of BIM status

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F24%3A00600584" target="_blank" >RIV/86652036:_____/24:00600584 - isvavai.cz</a>

Alternative codes found

RIV/68378050:_____/24:00604443 RIV/00216208:11110/24:10483793 RIV/61384399:31140/24:00060330 RIV/65269705:_____/24:00080340 RIV/00064165:_____/24:10483793

Result on the web

<a href="https://ashpublications.org/bloodadvances/article/8/13/3532/516030/Blockage-of-BCL-XL-overcomes-venetoclax-resistance" target="_blank" >https://ashpublications.org/bloodadvances/article/8/13/3532/516030/Blockage-of-BCL-XL-overcomes-venetoclax-resistance</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/bloodadvances.2024012906" target="_blank" >10.1182/bloodadvances.2024012906</a>

Result language

angličtina

Original language name

Blockage of BCL-XL overcomes venetoclax resistance across BCL2+lymphoid malignancies irrespective of BIM status

Original language description

Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30205 - Hematology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Blood Advances

ISSN

2473-9529

e-ISSN

2473-9537

Volume of the periodical

8

Issue of the periodical within the volume

13

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

12

Pages from-to

3532-3543

UT code for WoS article

001294402000001

EID of the result in the Scopus database

2-s2.0-85195879602