In patients with Chronic Lymphocytic Leukemia (CLL), there is an overgrowth of leukemic B-lymphocytes. This proliferation of B-cells requires inputs from the external microenvironment, which provides soluble molecules as well as physical interaction necessary for survival and proliferation. Studies have shown that the lymph nodes are one of such microenvironments. However, the specific interaction between lymph nodes and leukemic B-cell has not been elucidated. This study examines how fibroblastic reticular cells (FRCs) from the lymph nodes, and IL4 secreted by T-cells affect the proliferation and signaling of leukemic B cells.

When leukemic B cells were co-cultured with FRCs, there was a significant increase in the number of leukemic B cells. Moreover, the expression of CLECL1 surface protein is further increased on B-cells. Using recombinant CLECL1 protein, it was demonstrated that IL4 cytokine production increases in both naive T-cells and Th2 cells. In the presence of IL4, the level of proliferation of CLL B-cells is amplified. IL4 can also increase the expression of lymphotoxin (a cytokine) in B-cells and the lymphotoxin receptor on FRC. The expression of lymphotoxin is repressed in the presence of FRC. The expression of lymphotoxin in B-cells correlates with high levels of the adipocytokine CXCL13 by FRC. High level of CXCL13 subsequently correlates with reduced expression of CXCR5, which is required for B-cell migration and localization to the FRCs and is believed to play an important role in CLL cell proliferation. This study demonstrates that interactions with FRCs and IL4 is essential and necessary CLL progression.

References

1. Bénézech, Cécile., Mader, Emma., Desanti, Guillaume., Khan, Mahmood., Nakmura, Kyoko., White, Andrea., Ware, Carl F., Anderson, Graham., Caamáno, Jorge H. “Lymphotoxin-β Receptor Signaling through NF-B2-RelB Pathway Reprograms Adipocyte Precursors as Lymph Node Stromal Cells”. Immunity, 19 Oct., 2012.
2. Bürkle, Andrea., Niedermeier, Matthias., Schmitt-Gräff, Annette., Wierda, William G., Keating, Michael J., Burger, Jan A. “Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia”. Blood, 1 Nov., 2007.
3. Byrd, John C., Stilgenbauer, Stephen., Flinn, Ian W. “Chronic Lymphocytic Leukemia”. Hematology, 1 Jan., 2004.
4. Chen, Shih-Shih., Ravichandran, Priyadarshini., Ferrer, Gerardo., Mazzarello, Andrea Nicola., Palacios, Florencia., Ibrahim, Michael., Kieso, Yasmine., Barrientos, Jacqueline C., Clark, Edward., Sherry, Barbara., Burger, Jan A., Rai, Kanti., Chiorazzi, Nicholas. “Ibrutinib DIsrupts IL-4R - IL-4 Axis By Inhibiting IL-4R Signaling and Reversing Th2/Th1 Polarization through Diminished CLECL1 in CLL B Cells”. Blood, 8 Dec., 2017
5. Chen, Shih-Shih., Yan, Xiao-Jie., Cardillo, Martina., Ng, Anita., Shih, Andrew., Blanco, Gonzalo., King-Richards, Morgan., Chen, Yu-Ju., Kieso, Yasmine., Rhodes, Joanna M., Rai, Kanti R., Chiorazzi, Nicholas. “CLECL1+ CLL Cell: A Key Subset That Drives CLL Survival and Proliferation and Shapes a Th2-Biased Tumor Microenvironment”. Blood, 15 Nov., 2022.
6. Cortes-Selva, Diana., Ready, Andrew., Gibbs, Lisa., Rajwa, Bartek., Fairfax, Keke C. “IL-4 promotes stromal cell expansion and is critical for development of a type-2, but not a type 1 immune response”. National Library of Medicine, 3 Jan., 2019.
7. Fatima, Narjis., Crassini, Kyle R., Thurgood, Lauren., Shen, Yandong., Christopherson, Richard I., Kuss, Bryone., Mulligan, Stephen P., Best, Oliver Giles. “Therapeutic approaches and drug-resistance in chronic lymphocytic leukemia”. National Library of Medicine, 11 May 2020.
8. Herishanu, Yair., Peréz-Galán, Patricia., Liu, Delong., Biancotto, Angelique., Pittaluga, Stefania., Vire, Berengere., Gibellini, Federica., Njuguna, Ndegwa., Lee, Elinor., Stennett, Lawrence., Raghavachari, Nalini., Liu, Poching., McCoy, J. Philip., Raffeld, Mark., StetlerStevenson, Maryalice., Yuan, Constance., Sherry, Richard., Arthur, Diane C., Maric, Irina., White, Therese., Marti, Gerald E., Munson, Peter., Wilson, Wyndham H.,Wiestner. “The lymph node microenvironment promotes B-cell receptor signaling, NF-B activation, and tumor proliferation in chronic lymphocytic leukemia”. Blood, 13 Jan., 2011.
9. Hermansen, Johanne U., Yin, Yanping., Urban, Aleksandra., Myklebust, Camilla V., Karlsen, Linda., Melvold, Katrine., Tveita, Anders A., Taskén, Kjetil., Munthe, Ludvig A., Tjønnfjord, Geir E., Skánland, Sigrid S. “A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine”. Nature, 13 April, 2023.
10. Herndon, T M., Chen, S-S., Saba, N S., Vladez, J., Emerson, C., Gatmaitan, M., Tian, X., Hughes, T E., Sun, C., Arthur, D C., Stetler-Stevenson, M., Yuan, C M., Niemann, C U., Marti, G E., Aue, G., Soto, S., Farooqui, M Z H., Herman, S E M., Chiorazzi, N., Wiestner, A. “Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood”. Nature, 11 Jan., 2017.
11. Köhnke, Thomas., Wittmann, Veronica K., Bücklein, Veit L., Lichtenegger, Felix., Pasalic, Zlatana., Hiddermann, Wolfgang., Splekermann, Karsten., Subklewe, Marion. “Diagnosis of CLL revisited: increased specificity by a modified five-marker scoring system including CD200”. Wiley Online Library, 18 Aug., 2017.
12. Kwok, Marwan., Oldreive, Ceri., Rawstron, Andy C., Goel, Anshita., Papatzikas, Grigorios., Jones, Rhiannon E., Drennan, Samantha., Agathanggelou, Angelo., Sharma-Oates, Archana., Evans, Paul., Smith, Edward., Dala, Surita., Mao, Jingwen., Hallows, Robert., Gordon, Naheema., Hamada, Mayumi., Davies, Nicholas J., Parry, Helen., Beggs, Andrew D., Munir, Talha., Moreton, Paul., Paneesha, Shankara., Pratt, Guy., Taylor, A. Malcolm R., Forconic, Francesco., Baird, Duncan M., Cazier, Jean-Baptiste., Moss, Paul., Hillmen, Peter., Stankovic, Tatjana. “Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL”. Blood, 6 Feb., 2020.
13. Redaelli, A., Laskin, B L., Stephens, J M., Botteman, M F., Pashos, C L. “The clinical and epidemiological burden of chronic lymphocytic leukemia”. Wiley Online Library, 14 June, 2004.
14. Ryan, Elizabeth J., Marshall, Aaron J., Magaletti, Dario., Floyd, Helen., Draves, Kevin E., Olson, N Eric., Clark, Edward A. “Dendritic Cell-Associated Lectin-1: A Novel Dendritic Cell-Associated, C-Type Lectin-Like Molecule Enhances T-Cell Secretion of IL-4”. Immunology, 15 Nov., 2002.
15. Stebegg, Marisa., Kumar., Saumya D., Silva-Cayetano, Alyssa., Fonseca, Valter R., Linterman, Michelle A., Graca, Luis. “Regulation of the Germinal Center Response”. Frontiers, 25 Oct., 2018.
16. Textor, Johannes., Mandl, Judith N., de Boer, Rob J. “The Reticular Cell Network: A Robust Backbone for Immune Responses”. Plos Biology, 11 Oct., 2016.