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HIF-1? regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment.

ABSTRACT: Hypoxia-inducible transcription factors (HIFs) regulate a wide array of adaptive responses to hypoxia and are often activated in solid tumors and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1? is a novel regulator of the interaction of CLL cells with protective leukemia microenvironments and, in turn, is regulated by this interaction in a positive feedback loop that promotes leukemia survival and propagation. Through unbiased microarray analysis, we found that in CLL cells, HIF-1? regulates the expression of important chemokine receptors and cell adhesion molecules that control the interaction of leukemic cells with bone marrow and spleen microenvironments. Inactivation of HIF-1? impairs chemotaxis and cell adhesion to stroma, reduces bone marrow and spleen colonization in xenograft and allograft CLL mouse models, and prolongs survival in mice. Of interest, we found that in CLL cells, HIF-1? is transcriptionally regulated after coculture with stromal cells. Furthermore, HIF-1? messenger RNA levels vary significantly within CLL patients and correlate with the expression of HIF-1? target genes, including CXCR4, thus further emphasizing the relevance of HIF-1? expression to CLL pathogenesis.

SUBMITTER: Valsecchi R

PROVIDER: S-EPMC4946537 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment.

Valsecchi Roberta R Coltella Nadia N Belloni Daniela D Ponente Manfredi M Ten Hacken Elisa E Scielzo Cristina C Scarfò Lydia L Bertilaccio Maria Teresa Sabrina MT Brambilla Paola P Lenti Elisa E Martinelli Boneschi Filippo F Brendolan Andrea A Ferrero Elisabetta E Ferrarini Marina M Ghia Paolo P Tonon Giovanni G Ponzoni Maurilio M Caligaris-Cappio Federico F Bernardi Rosa R

Blood 20160129 16

Hypoxia-inducible transcription factors (HIFs) regulate a wide array of adaptive responses to hypoxia and are often activated in solid tumors and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1α is a novel regulator of the interaction of CLL cells with protective leukemia microenvironments and, in turn, is regulated by this interaction in a positive feedback loop that promotes leukemia survival ...[more]

PMID: 26825709

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Project description:Chronic lymphocytic leukemia (CLL) cells survive longer in vivo than in vitro, suggesting that the tissue microenvironment provides prosurvival signals to tumor cells. Primary and secondary lymphoid tissues are involved in the pathogenesis of CLL, and the role of these tissue microenvironments has not been explored completely. To elucidate host-tumor interactions, we performed gene expression profiling (GEP) of purified CLL cells from peripheral blood (PB; n = 20), bone marrow (BM; n = 18), and lymph node (LN; n = 15) and validated key pathway genes by real-time polymerase chain reaction, immunohistochemistry and/or TCL1 trans-genic mice. Gene signatures representing several pathways critical for survival and activation of B cells were altered in CLL cells from different tissue compartments. Molecules associated with the B-cell receptor (BCR), B cell-activating factor/a proliferation-inducing ligand (BAFF/APRIL), nuclear factor (NF)-κB pathway and immune suppression signature were enriched in LN-CLL, suggesting LNs as the primary site for tumor growth. Immune suppression genes may help LN-CLL cells to modulate antigen-presenting and T-cell behavior to suppress antitumor activity. PB CLL cells overexpressed chemokine receptors, and their cognate ligands were enriched in LN and BM, suggesting that a chemokine gradient instructs B cells to migrate toward LN or BM. Of several chemokine ligands, the expression of CCL3 was associated with poor prognostic factors. The BM gene signature was enriched with antiapoptotic, cytoskeleton and adhesion molecules. Interestingly, PB cells from lymphadenopathy patients shared GEP with LN cells. In Eμ-TCL1 transgenic mice (the mouse model of the disease), a high percentage of leukemic cells from the lymphoid compartment express key BCR and NF-κB molecules. Together, our findings demonstrate that the lymphoid microenvironment promotes survival, proliferation and progression of CLL cells via chronic activation of BCR, BAFF/APRIL and NF-κB activation while suppressing the immune response.

Dataset Information

HIF-1? regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment.

Publications

HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment.

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