Extracellular vesicles from chronic lymphocytic leukemia cells promote leukemia aggressiveness by inducing the differentiation of monocytes into nurse-like cells via an RNA-dependent mechanism

IF 7.6 2区医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2025-01-16 DOI:10.1002/hem3.70068

Nathan Dubois, David Van Morckhoven, Laurentijn Tilleman, Filip Van Nieuwerburgh, Dominique Bron, Laurence Lagneaux, Basile Stamatopoulos

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Abstract

Chronic lymphocytic leukemia (CLL) cells receive several stimuli from surrounding cells, such as B-cell receptor (BCR) stimulation, and can manipulate their microenvironment via extracellular vesicle (EV) release. Here, we investigated the small RNA content (microRNA and YRNA) of CLL-EVs from leukemic cells cultured with/without BCR stimulation. We highlight an increase of miR-155-5p, miR-146a-5p, and miR-132-3p in EVs and in cells after BCR stimulation (p < 0.05, n = 25). CLL-EVs were preferentially internalized by monocytes (p = 0.0019, n = 6) and able to deliver microRNAs and the hY4 RNA. Furthermore, BCR CLL-EV induced modifications in monocytes (shape change, microRNA and gene expression, secretome) suggesting nurse-like cell (NLC) differentiation, the tumor-associated macrophages of CLL. Functionally, monocytes treated with BCR CLL-EVs protect CLL cells from spontaneous apoptosis by pro-survival 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-EVs and that the addition of leukemic EVs to monocytes leads to monocyte differentiation into NLCs establishing a protective microenvironment that supports leukemic cell survival.

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慢性淋巴细胞白血病细胞外囊泡通过rna依赖机制诱导单核细胞向护士样细胞分化，从而促进白血病侵袭性。

慢性淋巴细胞白血病（CLL）细胞接受来自周围细胞的多种刺激，如b细胞受体（BCR）的刺激，并可以通过细胞外囊泡（EV）释放来操纵其微环境。在这里，我们研究了来自白血病细胞的小RNA含量（microRNA和YRNA），这些细胞在BCR刺激和不刺激下培养。我们强调了BCR刺激后ev和细胞中miR-155-5p、miR-146a-5p和miR-132-3p的增加（p n = 25）。cll - ev优先被单核细胞内化（p = 0.0019, n = 6），并能够传递microrna和hY4 RNA。此外，BCR CLL- ev诱导单核细胞发生改变（形状改变、microRNA和基因表达、分泌组），提示护士样细胞（NLC）分化，即CLL的肿瘤相关巨噬细胞。在功能上，单核细胞经BCR CLL- ev处理后，通过促生存细胞因子的产生保护CLL细胞免于自发凋亡，并诱导其迁移以及其他免疫细胞的迁移。我们最终通过转染实验报道了hY4能够诱导M2巨噬细胞分化的关键基因CCL24的表达。总之，我们发现BCR刺激改变了cll - ev的小RNA含量，并且将白血病ev添加到单核细胞中导致单核细胞分化为NLCs，建立了支持白血病细胞存活的保护性微环境。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

HemaSphere Medicine-Hematology

CiteScore

6.10

自引率

4.50%

发文量

2776

审稿时长

7 weeks

期刊介绍： HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.