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 5

S100A9Tg mice have increased accumulation and activation of MDSC and display dysplastic features that recapitulate human MDS pathology.

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S100A9Tg mice have increased accumulation and activation of MDSC and dis...
(A) Gr1+CD11b+ MDSC accumulation in BM-MNC isolated from S100A9Tg mice at 6, 18, or 24 weeks and S100A9KO or WT mice at both 6 and 24 weeks. (B) Percentage of MDSC from BM, spleen, and PBMC of S100A9Tg mice at 6, 18, and 24 weeks of age by flow cytometry. Spleen cells from B were also assayed against the maturation markers F4/80+Gr1– (C) and I-Ad+ (D). (E) FACS-sorted Gr-1+CD11b+ cells (+MDSC) from the BM of mice described in A remixed back with autologous 1 × 105 MDSC-negative population (containing HSPC, –MDSC) at 1:1 ratio for 14 days before evaluating colony formation. An MDSC-depleted population was used as the control. (F) MDSC from WT, S100A9Tg, and S100A9KO mice were FACS sorted and incubated in a 96-well plate for 24 hours after which IL-10 and TGF-β production were measured by ELISA. Comparison of the hematopathological analysis of WT (G–J) and S100A9Tg mice (K–N) Original magnification, ×200 (G and K); ×600 (H and L); ×1000 (J, I, M, and N). Detailed descriptions is in Methods. MDS-BM primary specimens were tested for the location of S100A9 in CD33+ cells (O) and CD34+ cells (P). Flow figures are representative of triplicate experiments.