The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications

Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications
Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications

NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.

0887-6924
Arruga, Francesca
9104b822-4467-4ed7-b914-2dd830beb917
Bracciamà, Valeria
32bdf784-f531-4c46-985b-6272e7cab681
Vitale, Nicoletta
72b855e2-f0a5-46b7-9c31-6817e869be67
Vaisitti, Tiziana
91a979a2-450f-4a33-ae43-8634908a2f56
Gizzi, Katiuscia
cff313d4-5f26-4058-8852-43169a464445
Yeomans, Alison
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Coscia, Marta
7ae299af-adc7-41fd-aa4b-b3ee6fe91d83
D'Arena, Giovanni
70024606-1ca7-4d41-ba16-1332478923a3
Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a
Allan, John N.
fac2e13a-f632-4f1d-8b59-14658dab87e2
Furman, Richard R.
f3544299-4295-4929-814f-5088f7081ad3
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Deaglio, Silvia
2e20f72c-3eb1-4388-a371-8cace561211c
Arruga, Francesca
9104b822-4467-4ed7-b914-2dd830beb917
Bracciamà, Valeria
32bdf784-f531-4c46-985b-6272e7cab681
Vitale, Nicoletta
72b855e2-f0a5-46b7-9c31-6817e869be67
Vaisitti, Tiziana
91a979a2-450f-4a33-ae43-8634908a2f56
Gizzi, Katiuscia
cff313d4-5f26-4058-8852-43169a464445
Yeomans, Alison
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Coscia, Marta
7ae299af-adc7-41fd-aa4b-b3ee6fe91d83
D'Arena, Giovanni
70024606-1ca7-4d41-ba16-1332478923a3
Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a
Allan, John N.
fac2e13a-f632-4f1d-8b59-14658dab87e2
Furman, Richard R.
f3544299-4295-4929-814f-5088f7081ad3
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Deaglio, Silvia
2e20f72c-3eb1-4388-a371-8cace561211c

Arruga, Francesca, Bracciamà, Valeria, Vitale, Nicoletta, Vaisitti, Tiziana, Gizzi, Katiuscia, Yeomans, Alison, Coscia, Marta, D'Arena, Giovanni, Gaidano, Gianluca, Allan, John N., Furman, Richard R., Packham, Graham, Forconi, Francesco and Deaglio, Silvia (2019) Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications. Leukemia. (doi:10.1038/s41375-019-0571-0).

Record type: Article

Abstract

NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.

This record has no associated files available for download.

More information

Accepted/In Press date: 17 July 2019
e-pub ahead of print date: 29 August 2019

Identifiers

Local EPrints ID: 436161
URI: http://eprints.soton.ac.uk/id/eprint/436161
ISSN: 0887-6924
PURE UUID: 74988713-e03d-4b77-b18c-ac420a3b0c9f
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

Catalogue record

Date deposited: 29 Nov 2019 17:31
Last modified: 26 Nov 2021 02:43

Export record

Altmetrics

Contributors

Author: Francesca Arruga
Author: Valeria Bracciamà
Author: Nicoletta Vitale
Author: Tiziana Vaisitti
Author: Katiuscia Gizzi
Author: Alison Yeomans
Author: Marta Coscia
Author: Giovanni D'Arena
Author: Gianluca Gaidano
Author: John N. Allan
Author: Richard R. Furman
Author: Graham Packham ORCID iD
Author: Silvia Deaglio

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×