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

D Farinello, M Wozińska, E Lenti, L Genovese, S Bianchessi, E Migliori, N Sacchetti, A Di Lillo, MTS Bertilaccio, C De Lalla, R Valsecchi, SB Gleave, D Lligé, C Scielzo, Laura Mauri, MG Ciampa, L Scarfò, R Bernardi, D Lazarevic, B Gonzalez-FarreL Bongiovanni, E Campo, A Cerutti, M Ponzoni, L Pattini, F Caligaris-Cappio, P Ghia, A Brendolan

Research output: Contribution to journalArticlepeer-review

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. © 2018 The Author(s).
Original languageEnglish
Article number1787
JournalNature Communications
Volume9
Issue number4
DOIs
Publication statusPublished - 2018

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