Myeloid-Related Protein S100A9 Induces Cellular Differentiation in Acute Myeloid Leukemia through TLR2 and TLR4 Receptors
Bibliographic record
Abstract
Abstract The myeloid-related proteins S100A8 (MRP8) and S100A9 (MRP14) are endogenous alarmins abundantly and constitutively expressed by myeloid cells (neutrophils, monocytes and immature myeloid cells). S100A8 and S100A9 proteins exist as homodimers but also associate to form the heterodimer calprotectin (S100A8/A9) and are up-regulated in several inflammatory diseases and human cancers. In patients with acute myeloid leukemia (AML), the concentration of S100A8/A9 in serum is elevated and the expression of S100A8 correlates with poor prognosis. However, the role of these proteins in hematologic malignancies is largely unknown. Here, we studied the roles of S100A8 and S100A9 in a mouse model ofAML induced by overexpression of Hoxa9 and Meis1 (H9M1). As observed in human, mice developing AML have a substantial increase in S100A8/A9 their serum (5.0µg/ml ± 1.0µg/mL vs 0.5µg/mL ± 0.1µg/mL for the control, p<0.0001). Using S100A8KO and S100A9KO mice, we demonstrated that S100A8/A9 proteins found in the sera are secreted by leukemic cells and not by the micro-environment. To investigate if secreted S100A8 and S100A9 proteins play a role in leukemogenesis, H9M1 AML were transplanted to secondary recipients were treated intraperitoneally (i.p) with anti-S100A8 or anti-S100A9 antibodies. Blocking S100A8 led to a marked delay in leukemia progression and significantly extended survival compared to control immunoglobulins (IgG) (31 days vs 39.5 days, p=0.010) with an increase of the CD11b+ Gr-1+ double positive population (78.8%±1.4 vs 90.1%±3, p=0.038). In contrast, no differences in overall survival were observed between control IgG and anti-S100A9 treated mice. In addition, we demonstrate that anti-S100A8 treatments reduced AML cell proliferation through the G0/G1 cell cycle arrest. Thus, blocking S100A8 reduces leukemogenesis and induced leukemic blast maturation in AML. To further investigate the roles of S100A8 and S100A9 in AML, we treated secondary H9M1 mice with S100A8 or S100A9 proteins i.p three times per week. Interestingly, injection of S100A8 had no effect on AML latency, but S100A9 treatment resulted in significant delays of leukemia symptoms suggesting an anti-leukemic activity (32 days vs 41 days, p=0.0045). The extent of increased survival induced by S100A9 treatment was similar to standard induction chemotherapy using combination of doxorubicin and cytarabine. Furthermore, S100A9 treatment led to significant cell cycle arrest and an increase of mature cells marker CD11band Gr-1 in bone marrow (76.6%± 1.0% vs 94.8 ± 1.2%, p<0.0001). Analysis of leukemic cells morphology confirmed that S100A9 modulates AML cells maturation. Since injection of the S100A9 protein and anti-S100A8 antibody had similar effect on AML progression and cellular differentiation, we postulated that cell differentiation is regulated by the balance between S100A9 and S100A8. To test the hypothesis, cells were cultured in vitro in presence of different ratio of S100A9 on S100A8. At high ratio (S100A9>S100A8), the percentage of CD11b+ Gr-1+ was increased compared to the control suggesting that leukemic cells underwent differentiation. Nevertheless, the augmentation of S100A8 level prevented the increases of CD11b+ Gr-1+ mediated by S100A9. To test the ability of S100A9 protein to promote terminal cell differentiation of human leukemia, human cord blood (CB) CD34+ cells were transduced with retrovirus expressing the oncogene MLL-AF9. In vitro, S100A9 induced a 10-fold up-regulation of CD14 expression in MLL-AF9 cells. More importantly, the increase of CD14 was associated with morphological changes typical of terminal differentiation into monocytes and then macrophages. To determine the receptor(s) involved in regulation of cellular differentiation induced by S100A9 in human AML, we followed CD14 expression in presence of anti-TLR neutralizing antibodies. Blockage of TLR4 and TLR2 prevented the differentiation of human leukemic cells mediated by S100A9. Taken together, we show that increasing the S100A9/S100A8 ratio in murine AML, either by anti-S100A8 antibody or recombinant S100A9 protein, prolong the survival of secondary mice in vivo by inducing differentiation on AML cells. We corroborated these data in human MLL-AF9 cells in vitro and show that S100A9 protein induces terminal differentiation through TLR receptors which could represent a new therapeutic target to explore. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".