Chronic lymphocytic leukaemia (CLL) is a B-cell cancer characterised by the clonal expansion of CD5+CD19+ malignant cells in secondary lymphoid organs, which allows close interaction between CLL and accessory cells, such as nurse-like cells, T cells, normal B cells, and stromal cells, providing stimuli for activation of crucial survival and proliferative signalling pathways in CLL cells. Given the resistance to therapy and shortcomings of current immunotherapies in CLL, further characterisation and understanding of the CLL interactions with their tumour environment is needed. By utilising the adoptive transfer model of Eμ-TCL1-tg mice, we systemically characterise the tumour microenvironment in CLL to decipher the interplay between lymphoid stromal cells and tumour cells and identify additional targetable interactions. We show that CLL progression is associated with profound remodelling the stromal environment, marked by the loss of follicular dendritic cells and T-zone reticular cells, and the emergency of activated and immunosuppressive stromal phenotypes, suggesting that stromal cells contribute not only to CLL survival but also to the functionality of surrounding accessory cells. Critically, in vivo depletion of CCL19+ stromal cells results in significant tumour growth arrest, providing functional validation that these stromal subsets actively sustain CLL proliferation. Overall, we identify a reciprocal interaction between CLL and stromal cells in the splenic microenvironment.