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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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 1

Increased accumulation and function of MDSC in BM of MDS patients.

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Increased accumulation and function of MDSC in BM of MDS patients. (A) P...
(A) Percentage of MDSC in the BM-MNC of MDS (n = 12), age-matched healthy (n = 8), and non-MDS cancer specimens (n = 8, P < 0.0001). (B) Chromosome 7 FISH of sorted MDSC or non-MDSC from MDS BM-MNC (n = 5, CEP7 is green and 7q31 orange). 3H-thymidine incorporation (C) and IFN-γ ELISA (D) of stimulated autologous T cells cocultured with sorted MDS-MDSC at 1:0.25 and 1:0.5 ratios (T cells:MDSC). Error bars denote SD of 3 separate patient samples tested in triplicate. (E) BrdU incorporation of stimulated T cells after admixing with autologous unsorted, MDSC depleted (–MDSC), or remixed (+MDSC) BM-MNC. Sorted MDSC from MDS or healthy donor BM tested for IL-10 (F), TGF-β (G), NO (H), and arginase (I) production after 24 hours of culture. (J) MDSC/erythroid precursor contact zone of admixed sorted MDS-MDSC and autologous erythroid precursors at a ratio of 1:3 (MDSC/erythroid precursor) by microscopy at 0 and 30 minutes. Cells were stained for CD71 (pink), CD235a (blue), CD33 (red), and granzyme B (green). (K) Sorted MDSC from MDS or healthy donors labeled with CD33 (red) and granzyme B (green) coincubated with purified autologous erythroid precursors (0 or 30 minutes) and monitored by microscopy. (L) Counts of MDSC-HPC conjugate mobilized granules. Original magnification, ×400 (B); ×600 (J and K). (M) Annexin V exposure on erythroid precursors (CD71+CD235a+) incubated with or without sorted autologous MDS-MDSC. (N) Colony-forming ability of unsorted, –MDSC, or remixed (+MDSC) MDS BM-MNC (ratio of 1:3). *P < 0.005; **P < 0.001; ***P < 0.05.