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 4

S100A9 signaling through CD33 in MDS BM is associated with MDSC activation and suppressive function.

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S100A9 signaling through CD33 in MDS BM is associated with MDSC activati...
Healthy BM cells infected with adenovirus containing GFP or CD33 expression vectors assessed by qPCR for the expression of IL-10 (A), TGF-β (C), ARG2 (E), or NOS2 (F), or by ELISA for IL-10 (B) and TGF-β (D). qPCR (G) and flow cytometry of GFP expression (H) determined transfection efficiency. Healthy BM cells’ RAGE, TLR4, CD33, or their combination were blocked prior to culturing cells by themselves or with 1 μg of S100A9 for 48 hours to determine IL-10 gene and protein expression (qPCR in the top and ELISA on the bottom) (I) or TGF-β gene and protein expression (J). (K) Silencing S100A8 and S100A9 expression in primary MDS-BM cells using specific shRNA (demonstrated by Western blot) inhibits the expression of IL-10 (L) and TGF-β (M). *P < 0.01; **P < 0.001, versus cells treated with control shRNA. (N) Blocking S100A8 and S100A9 expression by specific shRNA promotes colony formation in BM cells isolated from patients with MDS. *P < 0.05, versus cells treated with control shRNA. In all experiments, error bars represent the SEM of triplicate determination with 3 separate primary specimens.