Membrane Type-Matrix Metalloproteinases (MT-MMPs) Are Expressed in Acute Myeloid Leukemia Cells and Are Upregulated by TNF-α.
Bibliographic record
Abstract
Abstract Membrane type-matrix metalloproteinases (MT-MMPs) play a key role in tumor cell progression and metastasis but their role in hematological malignancy and leukemic cell dissemination is still unclear. To date, six MT-MMPs have been identified, of which four (MT1-, MT2-, MT3- and MT5-MMP) possess a trans-membrane domain that tethers the enzyme to the plasma membrane and two (MT4- and MT6-MMP) are anchored to the cell surface via a glycophosphatidyl inositol domain. MT-MMPs are known to activate pro-forms of MMPs. We examined the expression of all six MT-MMPs in 13 myeloid and lymphoid cell lines using RT-PCR, Western blotting and FACS. We found that MT1-MMP was expressed on most of the cell lines tested, MT2-MMP was expressed in myeloid cell lines such as THP-1, HEL, K562 and U937, and in T cell lines such as Jurkat and CEM, but not in any of the tested B cell lines, MT3-MMP was not expressed in any of the cell lines except for THP-1, MT4-MMP was strongly expressed in all myeloid but not lymphoid cell lines and MT5-MMP and MT6-MMP were expressed in most of the myeloid cell lines. Next, we examined the expression of all six MT-MMPs in primary AML samples and found that MT1-MMP is expressed in 20 out of 24 AML patient samples as detected by RT-PCR and Western blotting, MT2-MMP and MT4-MMP were expressed in 21 and 22 out of 24 samples, respectively, and MT6-MMP was expressed in 17 out of the 17 samples tested. In contrast, MT3- and MT5-MMPs were not found in the primary AML samples. Zymographic analysis showed that the pro form of MMP-2 was secreted in media conditioned by AML blasts and became activated only when these AML blasts were co-cultured with BM stromal cells. Since TNF-α is endogenously secreted by AML blasts we next stimulated these cells with human recombinant TNF-α and found strong upregulation of MT1-MMP and MT6-MMP. Moreover, zymography demonstrated that TNF-α-stimulated AML blasts are more potent in activation of pro-MMP-2 than unstimulated cells, indicating that activation may occur via upregulation of MT-MMPs. Furthermore, we found that TNF-α stimulation led to stronger upregulation/induction of MT1- and MT2-MMPs in CD34+ cells than in CD34- cells isolated from AML patients. In conclusion, we report here for the first time that MT1-, 2-, 4- and 6-MMPs are expressed in AML blasts and suggest that these MT-MMPs may contribute to the invasive phenotype of this malignancy.
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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 | 0.000 |
| 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".