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.

A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression / D. Farinello, M. Wozinska, E. Lenti, L. Genovese, S. Bianchessi, E. Migliori, N. Sacchetti, A. Di Lillo, M.T.S. Bertilaccio, C. De Lalla, R. Valsecchi, S.B. Gleave, D. Llige, C. Scielzo, L. Mauri, M.G. Ciampa, L. Scarfo, R. Bernardi, D. Lazarevic, B. Gonzalez-Farre, L. Bongiovanni, E. Campo, A. Cerutti, M. Ponzoni, L. Pattini, F. Caligaris-Cappio, P. Ghia, A. Brendolan. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 9:1(2018 May), p. 1787.

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

Di Lillo A.;Mauri L.;Ciampa M. G.;
2018-05

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.
Settore BIO/10 - Biochimica
Settore BIO/11 - Biologia Molecolare
Settore MED/06 - Oncologia Medica
NATURE COMMUNICATIONS
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/580648
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