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

作者：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; Gleave Sabrina Bascones; Llige David; Scielzo Cristina; Mauri Laura; Ciampa Maria Grazia; Scarfo Lydia; Bernardi Rosa; Lazarevic Dejan; Gonzalez Farre Blanca; Bongiovanni Lucia; Campo Elias; Cerutti Andrea; Ponzoni Maurilio; Pattini Linda; Caligaris Cappio Federico

来源：Nature Communications, 2018, 9(1): 1787.

DOI：10.1038/s41467-018-04150-7

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 Rar gamma 2 and RXR alpha, 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.

• 出版日期2018-5-3