Induction of myelodysplasia by myeloid-derived suppressor cells
Xianghong Chen, … , Alan List, Sheng Wei
Xianghong Chen, … , Alan List, Sheng Wei
Published October 15, 2013
Citation Information: J Clin Invest. 2013;123(11):4595-4611. https://doi.org/10.1172/JCI67580.
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Research Article Hematology

Induction of myelodysplasia by myeloid-derived suppressor cells

Abstract

Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.

Authors

Xianghong Chen, Erika A. Eksioglu, Junmin Zhou, Ling Zhang, Julie Djeu, Nicole Fortenbery, Pearlie Epling-Burnette, Sandra Van Bijnen, Harry Dolstra, John Cannon, Je-in Youn, Sarah S. Donatelli, Dahui Qin, Theo De Witte, Jianguo Tao, Huaquan Wang, Pingyan Cheng, Dmitry I. Gabrilovich, Alan List, Sheng Wei

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Figure 2

CD33 signals to enhance MDSC suppressive functions.

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CD33 signals to enhance MDSC suppressive functions. (A) BM-MNC from MDS ...
(A) BM-MNC from MDS patients (n = 12), age-matched healthy donors (n = 8), and non-MDS cancers (n = 8) were analyzed for CD33’s MFI. *P < 0.0005. (B) Concentration of IL-10, TGF-β, and VEGF from the supernatant of CD33 (or isotype) crosslinked U937 cells. Bars represent mean ± SEM of 3 wells on 3 separate experiments. (C) BM-MNC were isolated from healthy donors and infected with an adenoviral vector containing either GFP (Ad-GFP) or CD33 (Ad-CD33) for 72 hours before flow cytometric analysis of the mature myeloid markers, CD11c, CD80, and CCR7, with noninfected cells as a control (data not shown). (D) BFU and (E) CFU colony-forming assay. After sorting out MDSC from the BM of MDS patients, the remaining MDSC-negative cells were cultured with MDSC that had been mock infected or infected with LV containing nontargeted shRNA or CD33 shRNA (shCD33) for 14 days. The colony formation assay was performed. The MDSC were also cultured for 72 hours after infection with LV containing constructs described above before culturing with MDSC-negative BM cells. *P < 0.001, versus cells treated with control shRNA. The supernatants were collected and assayed for IL-10 (F) and TGF-β (G) by ELISA. *P < 0.05, versus cells treated with control shRNA. (H) The shCD33-treated cells were also analyzed for arginase activity. *P < 0.05, versus cells treated with control shRNA.