Publications

Authors:

Rigo, Antonella; Vaisitti, Tiziana; Laudanna, Carlo; Terrabuio, Eleonora; Micillo, Matilde; Frusteri, Cristina; D'Ulivo, Beatrice; Merigo, Flavia; Sbarbati, Andrea; Mellert, Kevin; Möeller, Peter; Montresor, Alessio; Di Napoli, Arianna; Cirombella, Roberto; Butturini, Elena; Massaia, Massimo; Constantin, Gabriela; Vinante, Fabrizio; Deaglio, Silvia; Ferrarini, Isacco

Title:

Decreased apoptotic priming and loss of BCL-2 dependence are functional hallmarks of Richter's syndrome

Year:

2024

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

Sì

Name of journal:

CELL DEATH & DISEASE

ISSN of journal:

2041-4889

N° Volume:

15

Number or Folder:

5

Page numbers:

1-15

Keyword:

Richter's syndrome (RS); chronic lymphocytic leukemia (CLL)

Short description of contents:

Richter's syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade B-cell malignancy. Molecular and functional studies have pointed out that CLL cells are close to the apoptotic threshold and dependent on BCL-2 for survival. However, it remains undefined how evasion from apoptosis evolves during disease transformation. Here, we employed functional and static approaches to compare the regulation of mitochondrial apoptosis in CLL and RS. BH3 profiling of 17 CLL and 9 RS samples demonstrated that RS cells had reduced apoptotic priming and lower BCL-2 dependence than CLL cells. While a subset of RS was dependent on alternative anti-apoptotic proteins and was sensitive to specific BH3 mimetics, other RS cases harbored no specific anti-apoptotic addiction. Transcriptomics of paired CLL/RS samples revealed downregulation of pro-apoptotic sensitizers during disease transformation. Albeit expressed, effector and activator members were less likely to colocalize with mitochondria in RS compared to CLL. Electron microscopy highlighted reduced cristae width in RS mitochondria, a condition further promoting apoptosis resistance. Collectively, our data suggest that RS cells evolve multiple mechanisms that lower the apoptotic priming and shift the anti-apoptotic dependencies away from BCL-2, making direct targeting of mitochondrial apoptosis more challenging after disease transformation.

Web page:

https://doi.org/10.1038/s41419-024-06707-5

Product ID:

139666

Handle IRIS:

11562/1126486

Last Modified:

January 30, 2025

Bibliographic citation:

Rigo, Antonella; Vaisitti, Tiziana; Laudanna, Carlo; Terrabuio, Eleonora; Micillo, Matilde; Frusteri, Cristina; D'Ulivo, Beatrice; Merigo, Flavia; Sbarbati, Andrea; Mellert, Kevin; Möeller, Peter; Montresor, Alessio; Di Napoli, Arianna; Cirombella, Roberto; Butturini, Elena; Massaia, Massimo; Constantin, Gabriela; Vinante, Fabrizio; Deaglio, Silvia; Ferrarini, Isacco, Decreased apoptotic priming and loss of BCL-2 dependence are functional hallmarks of Richter's syndrome «CELL DEATH & DISEASE» , vol. 15 , n. 5 , 2024 , pp. 1-15

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