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Chronic Lymphocytic Leukemia
SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation
Federico Pozzo,1 Tamara Bittolo,1 Erika Tissino,1 Filippo Vit,1,2
Elena Vendramini,1 Luca Laurenti,3 Giovanni D’Arena,4 Jacopo Olivieri,5 Gabriele Pozzato,6 Francesco Zaja,6 Annalisa Chiarenza,7
Francesco Di Raimondo,7 Antonella Zucchetto,1 Riccardo Bomben,1 Francesca Maria Rossi,1 Giovanni Del Poeta,8 Michele Dal Bo1
and Valter Gattei1
1Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano; 2Department of Life Science, University of Trieste, Trieste; 3Hematology Institute, Catholic University of the Sacred Heart, Fondazione Policlinico A. Gemelli, Rome; 4Hematology Service, S. Luca Hospital, Vallo Della Lucania; 5Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi", Azienda Sanitaria Universitaria Integrata di Udine, Udine; 6Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste; 7Division of Hematology, Ferrarotto Hospital, Catania and 8Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Rome, Italy
ABSTRACT
Chronic lymphocytic leukemia (CLL) is characterized by low CD20 expression, in part explained by an epigenetic-driven downregu- lation triggered by mutations of the NOTCH1 gene. In the pres- ent study, by taking advantage of a wide and well-characterized CLL cohort (n=537), we demonstrate that CD20 expression is downregulated in SF3B1-mutated CLL to an extent similar to NOTCH1-mutated CLL. In fact, SF3B1-mutated CLL cells show common features with NOTCH1- mutated CLL cells, including a gene expression profile enriched in NOTCH1-related gene sets and elevated expression of the active intracy- toplasmic NOTCH1. Activation of the NOTCH1 signaling and down- regulation of surface CD20 in SF3B1-mutated CLL cells correlate with overexpression of an alternatively spliced form of DVL2, a component of the Wnt pathway and negative regulator of the NOTCH1 pathway. These findings were confirmed by separately analyzing the CD20dim and CD20bright cell fractions from SF3B1-mutated cases as well as by DVL2 knockout experiments in CLL-like cell models. Together, the clinical and biological features that characterize NOTCH1-mutated CLL may also be recapitulated in SF3B1-mutated CLL, contributing to explain the poor prognosis of this CLL subset and providing the rationale for expanding therapies based on novel agents to SF3B1-mutated CLL.
Introduction
Chronic lymphocytic leukemia (CLL) is characterized by pronounced clinical and biological heterogeneity.1 Therapy regimens that include monoclonal antibodies against CD20 are widely used, both as single agents and in combination2,3 although, in specific CLL subsets, the efficacy of anti-CD20 therapy may be reduced by the peculiar dimmer expression of CD20 in CLL4-6 compared to other lymphoproliferative disorders.7
A number of factors have been variously associated with CD20 regulation, e.g., NF-kB signaling, the CXCR4 pathway, B-cell receptor (BCR) signaling, histone deacetylases and activity of multiple transcription factors (such as IRF4, NF-kB, PU.1, OCT1/2);8 in addition, CD20 expression in CLL can be also affected by mutations of the NOTCH1 gene whose presence, detected in up to 25% of cases,9 has been associated with clinical resistance to anti-CD20 immunotherapy both in clinical trials and real-world scenarios.10-12 We previously demonstrated that the
Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3125-3135
Correspondence:
FEDERICO POZZO
federico.pozzo@cro.it
VALTER GATTEI
vgattei@cro.it
Received: June 11, 2020. Accepted: October 6, 2020. Pre-published: October 29, 2020.
https://doi.org/10.3324/haematol.2020.261891 ©2021 Ferrata Storti Foundation
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