TY - JOUR
T1 - A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression
AU - Farinello, Diego
AU - Wozińska, Monika
AU - Lenti, Elisa
AU - Genovese, Luca
AU - Bianchessi, Silvia
AU - Migliori, Edoardo
AU - Sacchetti, Nicolò
AU - Di Lillo, Alessia
AU - Bertilaccio, Maria Teresa Sabrina
AU - De Lalla, Claudia
AU - Valsecchi, Roberta
AU - Gleave, Sabrina Bascones
AU - Lligé, David
AU - Scielzo, Cristina
AU - Mauri, Laura
AU - Ciampa, Maria Grazia
AU - Scarfò, Lydia
AU - Bernardi, Rosa
AU - Lazarevic, Dejan
AU - Gonzalez-Farre, Blanca
AU - Bongiovanni, Lucia
AU - Campo, Elias
AU - Cerutti, Andrea
AU - Ponzoni, Maurilio
AU - Pattini, Linda
AU - Caligaris-Cappio, Federico
AU - Ghia, Paolo
AU - Brendolan, Andrea
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-04150-7
DO - 10.1038/s41467-018-04150-7
M3 - Article
C2 - 29725010
AN - SCOPUS:85046547720
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1787
ER -