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

Diego FarinelloMonika WozińskaElisa LentiLuca GenoveseSilvia BianchessiEdoardo MiglioriNicolò SacchettiAlessia di LilloMaria Teresa Sabrina BertilaccioClaudia de LallaRoberta ValsecchiSabrina Bascones GleaveDavid LligéCristina ScielzoLaura MauriMaria Grazia CiampaLydia ScarfòRosa BernardiDejan LazarevićBlanca Gonzalez-FarreLucia BongiovanniElias CampoAndrea CeruttiMaurilio PonzoniLinda PattiniFederico Caligaris-CappioPaolo GhiaAndrea Brendolan
Published in: Nature communications (2018)
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.
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