A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression

Diego Farinello, Monika Wozińska, Elisa Lenti, Luca Genovese, Silvia Bianchessi, Edoardo Migliori, Nicolò Sacchetti, Alessia di Lillo, Maria Teresa Sabrina Bertilaccio, Claudia de Lalla, Roberta Valsecchi, Sabrina Bascones Gleave, David Lligé, Cristina Scielzo, Laura Mauri, Maria Grazia Ciampa, Lydia Scarfò, Rosa Bernardi, Dejan Lazarevic, Blanca Gonzalez-Farre, Lucia Bongiovanni, Elias Campo, Andrea Cerutti, Maurilio Ponzoni, Linda Pattini, Federico Caligaris-Cappio, Paolo Ghia and Andrea Brendolan ()
Additional contact information
Diego Farinello: IRCCS, San Raffaele Scientific Institute
Monika Wozińska: IRCCS, San Raffaele Scientific Institute
Elisa Lenti: IRCCS, San Raffaele Scientific Institute
Luca Genovese: IRCCS, San Raffaele Scientific Institute
Silvia Bianchessi: IRCCS, San Raffaele Scientific Institute
Edoardo Migliori: IRCCS, San Raffaele Scientific Institute
Nicolò Sacchetti: IRCCS, San Raffaele Scientific Institute
Alessia di Lillo: IRCCS, San Raffaele Scientific Institute
Maria Teresa Sabrina Bertilaccio: IRCCS, San Raffaele Scientific Institute
Claudia de Lalla: IRCCS, San Raffaele Scientific Institute
Roberta Valsecchi: IRCCS, San Raffaele Scientific Institute
Sabrina Bascones Gleave: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
David Lligé: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Cristina Scielzo: IRCCS, San Raffaele Scientific Institute
Laura Mauri: University of Milan
Maria Grazia Ciampa: University of Milan
Lydia Scarfò: IRCCS, San Raffaele Scientific Institute
Rosa Bernardi: IRCCS, San Raffaele Scientific Institute
Dejan Lazarevic: IRCCS, San Raffaele Scientific Institute
Blanca Gonzalez-Farre: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic and University of Barcelona
Lucia Bongiovanni: Pathology Unit, IRCCS San Raffaele Scientific Institute
Elias Campo: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic and University of Barcelona
Andrea Cerutti: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Maurilio Ponzoni: Pathology Unit, IRCCS San Raffaele Scientific Institute
Linda Pattini: Politecnico di Milano
Federico Caligaris-Cappio: IRCCS, San Raffaele Scientific Institute
Paolo Ghia: IRCCS, San Raffaele Scientific Institute
Andrea Brendolan: IRCCS, San Raffaele Scientific Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. However, the nature of the stromal cells and molecular pathways involved remain largely unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in stromal cells causes deregulation of genes associated with adhesion, tissue organization and chemokine secretion including the B-cell chemokine CXCL13. Notably, reducing retinoic acid precursors from the diet or inhibiting RA-signaling through retinoid-antagonist therapy prolong survival by preventing dissemination of leukemia cells into lymphoid tissues. Furthermore, mouse and human leukemia cells could be distinguished from normal B-cells by their increased expression of Rarγ2 and RXRα, respectively. These findings establish a role for retinoids in murine CLL pathogenesis, and provide new therapeutic strategies to target the microenvironment and to control disease progression.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04150-7

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DOI: 10.1038/s41467-018-04150-7

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