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

D Farinello, M Wozińska, E Lenti, L Genovese, S Bianchessi, E Migliori, N Sacchetti, A Di Lillo, MTS Bertilaccio, C De Lalla, R Valsecchi, SB Gleave, D Lligé, C Scielzo, Laura Mauri, MG Ciampa, L Scarfò, R Bernardi, D Lazarevic, B Gonzalez-FarreL Bongiovanni, E Campo, A Cerutti, M Ponzoni, L Pattini, F Caligaris-Cappio, P Ghia, A Brendolan

Research output: Contribution to journalArticle

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. © 2018 The Author(s).
Original languageEnglish
Article number1787
JournalNature Communications
Volume9
Issue number4
DOIs
Publication statusPublished - 2018

Fingerprint

leukemias
Retinoids
B-Cell Chronic Lymphocytic Leukemia
Crosstalk
Tretinoin
crosstalk
progressions
Leukemia
B-Lymphocytes
Cells
Stromal Cells
acids
Chemokine CXCL13
Chemical activation
Tissue Adhesions
Tissue
Disease control
Deregulation
Survival
Lymphocytes

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A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression. / Farinello, D; Wozińska, M; Lenti, E; Genovese, L; Bianchessi, S; Migliori, E; Sacchetti, N; Di Lillo, A; Bertilaccio, MTS; De Lalla, C; Valsecchi, R; Gleave, SB; Lligé, D; Scielzo, C; Mauri, Laura; Ciampa, MG; Scarfò, L; Bernardi, R; Lazarevic, D; Gonzalez-Farre, B; Bongiovanni, L; Campo, E; Cerutti, A; Ponzoni, M; Pattini, L; Caligaris-Cappio, F; Ghia, P; Brendolan, A.

In: Nature Communications, Vol. 9, No. 4, 1787, 2018.

Research output: Contribution to journalArticle

Farinello, D, Wozińska, M, Lenti, E, Genovese, L, Bianchessi, S, Migliori, E, Sacchetti, N, Di Lillo, A, Bertilaccio, MTS, De Lalla, C, Valsecchi, R, Gleave, SB, Lligé, D, Scielzo, C, Mauri, L, Ciampa, MG, Scarfò, L, Bernardi, R, Lazarevic, D, Gonzalez-Farre, B, Bongiovanni, L, Campo, E, Cerutti, A, Ponzoni, M, Pattini, L, Caligaris-Cappio, F, Ghia, P & Brendolan, A 2018, 'A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression', Nature Communications, vol. 9, no. 4, 1787. https://doi.org/10.1038/s41467-018-04150-7
Farinello, D ; Wozińska, M ; Lenti, E ; Genovese, L ; Bianchessi, S ; Migliori, E ; Sacchetti, N ; Di Lillo, A ; Bertilaccio, MTS ; De Lalla, C ; Valsecchi, R ; Gleave, SB ; Lligé, D ; Scielzo, C ; Mauri, Laura ; Ciampa, MG ; Scarfò, L ; Bernardi, R ; Lazarevic, D ; Gonzalez-Farre, B ; Bongiovanni, L ; Campo, E ; Cerutti, A ; Ponzoni, M ; Pattini, L ; Caligaris-Cappio, F ; Ghia, P ; Brendolan, A. / A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression. In: Nature Communications. 2018 ; Vol. 9, No. 4.
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title = "A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression",
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. {\circledC} 2018 The Author(s).",
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AU - Farinello, D

AU - Wozińska, M

AU - Lenti, E

AU - Genovese, L

AU - Bianchessi, S

AU - Migliori, E

AU - Sacchetti, N

AU - Di Lillo, A

AU - Bertilaccio, MTS

AU - De Lalla, C

AU - Valsecchi, R

AU - Gleave, SB

AU - Lligé, D

AU - Scielzo, C

AU - Mauri, Laura

AU - Ciampa, MG

AU - Scarfò, L

AU - Bernardi, R

AU - Lazarevic, D

AU - Gonzalez-Farre, B

AU - Bongiovanni, L

AU - Campo, E

AU - Cerutti, A

AU - Ponzoni, M

AU - Pattini, L

AU - Caligaris-Cappio, F

AU - Ghia, P

AU - Brendolan, A

PY - 2018

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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. © 2018 The Author(s).

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. © 2018 The Author(s).

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