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Here, we investigated the small RNA content (microRNA and YRNA) of CLL\u2010EVs from leukemic cells cultured with\/without BCR stimulation. We highlight an increase of miR\u2010155\u20105p, miR\u2010146a\u20105p, and miR\u2010132\u20103p in EVs and in cells after BCR stimulation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05, <jats:italic>n<\/jats:italic>\u2009=\u200925). CLL\u2010EVs were preferentially internalized by monocytes (<jats:italic>p<\/jats:italic>\u2009=\u20090.0019, <jats:italic>n<\/jats:italic>\u2009=\u20096) and able to deliver microRNAs and the hY4 RNA. Furthermore, BCR CLL\u2010EV induced modifications in monocytes (shape change, microRNA and gene expression, secretome) suggesting nurse\u2010like cell (NLC) differentiation, the tumor\u2010associated macrophages of CLL. Functionally, monocytes treated with BCR CLL\u2010EVs protect CLL cells from spontaneous apoptosis by pro\u2010survival cytokine production and induce their migration as well as the migration of other immune cells. We finally reported by transfection experiments that hY4 is able to induce the expression of CCL24, a key gene in M2 macrophage differentiation. In conclusion, we showed that BCR stimulation modifies the small RNA content of CLL\u2010EVs and that the addition of leukemic EVs to monocytes leads to monocyte differentiation into NLCs establishing a protective microenvironment that supports leukemic cell survival.<\/jats:p>","DOI":"10.1002\/hem3.70068","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T08:11:58Z","timestamp":1737015118000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Extracellular vesicles from chronic lymphocytic leukemia cells promote leukemia aggressiveness by inducing the differentiation of monocytes into nurse\u2010like cells via an RNA\u2010dependent mechanism"],"prefix":"10.1002","volume":"9","author":[{"given":"Nathan","family":"Dubois","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Cell Therapy Universit\u00e9 Libre de Bruxelles (ULB), Jules Bordet Institute Brussels 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