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-FarreLucia Bongiovanni, Elias Campo, Andrea Cerutti, Maurilio Ponzoni, Linda Pattini, Federico Caligaris-Cappio, Paolo Ghia, Andrea Brendolan

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Article number1787
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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