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- Title
A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression.
- Authors
Farinello, Diego; Wozinska, Monika; Lenti, Elisa; Genovese, Luca; Bianchessi, Silvia; Migliori, Edoardo; Sacchetti, Nicolo; di Lillo, Alessia; Bertilaccio, Maria Teresa Sabrina; de Lalla, Claudia; Valsecchi, Roberta; Bascones Gleave, Sabrina; Lligé, David; Mauri, Laura; Scielzo, Cristina; Ciampa, Maria Grazia; Scarfo, Lydia; Bernardi, Rosa; Lazarevic, Dejan; Gonzalez-Farre, Blanca
- 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.
- Subjects
CHRONIC lymphocytic leukemia; PATHOLOGY; LYMPHOID tissue; LYMPHOCYTIC leukemia; STROMAL cells; B cells
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-04150-7