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Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment, particularly bone marrow\u2010derived stromal cells (BMSCs). Our three\u2010dimensional (3D) approach allows us to investigate spatially defined, mutual direct cell\u2013cell interactions between CLL B cells, autologous T cells, and BMSCs, forming complex scaffold\u2010like structures reminiscent of in vivo conditions. Here, we observe that CLL B cells localized in the core regions of 3D structures upregulate the AP\u20101 transcription factor complex, which confers significant protection against therapy\u2010induced cell death. Additionally, regulatory T cells (T\n                    <jats:sub>reg<\/jats:sub>\n                    ) and follicular T helper cells (T\n                    <jats:sub>fH<\/jats:sub>\n                    ) are more abundant in the core regions. CLL B cells, in turn, induce contact\u2010mediated reprogramming of BMSCs, resulting in a novel, distinct BMSC population with inflammation, bone immune evasion, and cancer\u2010associated fibroblast\u2010like features. Our findings reveal critical mechanisms by which CLL cells exploit the TME to drive pathogenesis and therapeutic resistance using realistic 3D setups, highlighting the potential of targeting AP\u20101 and the stromal compartment in future treatment strategies.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70199","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T19:11:08Z","timestamp":1755112268000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["3D Tumor microenvironment interaction reveals AP\u20101 complex regulation and contact\u2010mediated reprogramming of bone marrow stromal cells in chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"9","author":[{"given":"Jana","family":"Lindacher","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 5, Hematology and Oncology Universit\u00e4tsklinikum Erlangen, 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