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.
Highlights
In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion
Recent work in mice demonstrated that few hours after injection into wild-type recipients, Eμ-TCL1 CLL cells migrate to follicles in a CXCR5-dependent manner and engage a cross-talk with follicular stromal cells via LTβR, resulting in CXCL13 secretion by stromal cells, leukemia activation, and proliferation[25]
To investigate the molecular pathways activated upon stromaleukemia cross-talk, including those implicated in chemokine secretion, we performed a microarray analysis using mRNA purified from a murine spleen stromal cell line cultured for 48 h with either murine Eμ-TCL1 CLL cells or control splenic B cells (Fig. 1a)
Summary
In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. Mouse and human leukemia cells could be distinguished from normal B-cells by their increased expression of Rarγ[2] 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. Chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in Western countries, is characterized by the expansion of mature CD5+ B cells in protective microenvironmental niches of secondary lymphoid organs (SLOs) and bone marrow (BM) In these tissues, the interactions between leukemia and cells of the microenvironment promote tumor cell survival, chemoresistance, and disease progression[1,2,3]. We further demonstrate that blocking RA-signaling controls disease progression and prolongs survival, opening to novel potential therapeutic strategies to treat CLL by targeting stroma–leukemia interactions through inhibition of retinoid signaling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
