Enhanced IL-9 secretion by p66Shc-deficient CLL cells modulates the chemokine landscape of the stromal microenvironment

间质细胞 趋化因子 慢性淋巴细胞白血病 肿瘤微环境 癌症研究 归巢(生物学) 生物 免疫学 基质细胞衍生因子1 基质 白血病 细胞生物学 炎症 免疫系统 CXCR4型 免疫组织化学 生态学
作者
Laura Patrussi,Noemi Manganaro,Nagaja Capitani,Cristina Ulivieri,Vanessa Tatangelo,Francesca Libonati,Francesca Finetti,Federica Frezzato,Andrea Visentin,Mario Milco D’Elios,Livio Trentin,Gianpietro Semenzato,Cosima T. Baldari
出处
期刊:Blood [American Society of Hematology]
卷期号:137 (16): 2182-2195 被引量:8
标识
DOI:10.1182/blood.2020005785
摘要

Abstract The stromal microenvironment is central to chronic lymphocytic leukemia (CLL) pathogenesis. How leukemic cells condition the stroma to enhance its chemoattractant properties remains elusive. Here, we show that mouse and human CLL cells promote the contact-independent stromal expression of homing chemokines. This function was strongly enhanced in leukemic cells from Eμ-TCL1 mice lacking the pro-oxidant p66Shc adaptor, which develop an aggressive disease with organ infiltration. We identified interleukin-9 (IL-9) as the soluble factor, negatively modulated by p66Shc, that is responsible for the chemokine-elevating activity of leukemic cells on stromal cells. IL-9 blockade in Eμ-TCL1/p66Shc−/− mice resulted in a decrease in the nodal expression of homing chemokines, which correlated with decreased leukemic cell invasiveness. IL-9 levels were found to correlate inversely with residual p66Shc in p66Shc-deficient human CLL cells (n = 52 patients). p66Shc reconstitution in CLL cells normalized IL-9 expression and neutralized their chemokine-elevating activity. Notably, high IL-9 expression in CLL cells directly correlates with lymphadenopathy, liver infiltration, disease severity, and overall survival, emerging as an independent predictor of disease outcome. Our results demonstrate that IL-9 modulates the chemokine landscape in the stroma and that p66Shc, by regulating IL-9 expression, fine tunes the ability of leukemic cells to shape the microenvironment, thereby contributing to CLL pathogenesis.
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