Abstract
Secreted matrix metalloproteinases (MMP)-2 and MMP-9 and membrane-anchored aminopeptidase-N/CD13 are abnormally expressed in human acute myeloid leukaemia (AML). We previously showed that CD13 ligation by anti-CD13 monoclonal antibodies can induce apoptosis in AML cells. Here, we assessed ADAM17 expression in primary blood blasts CD13+CD33+ from patients with AML. Primary AML cells expressed ADAM17 transcript and its surface expression was higher in subtype M4 (myelomonocytic) and M5 (monocytic) AML specimens than in M0 and M1/M2 (early and granulocytic) specimens. In AML cell lines defining distinct AML subfamilies (HL-60/M2, NB4/M3, THP-1/M5, U937/M5) and primary AML cells cultured ex vivo, anti-CD13 antibodies downregulated surface CD13 and ADAM17 without affecting MMP-2/-9 release. Knockdown of CD13 by siRNA prevented anti-CD13-mediated ADAM17 downregulation, indicating that CD13 is required for ADAM17 downregulation. Soluble ADAM17 was not detected in the medium of anti-CD13 treated cells, suggesting that ADAM17 was not shed. After ligation by anti-CD13, CD13 and ADAM17 were internalized. Subsequently, we found that ADAM17 interacts with CD13. We postulate that the interaction of ADAM17 with CD13 and its downregulation following CD13 engagement has important implications in AML for the known roles of ADAM17 in tumour-associated cell growth, migration and invasion.
Highlights
Acute myeloid leukaemia (AML) is a clinically and genetically heterogeneous haematopoietic cancer characterized by the clonal accumulation of immature myeloid precursors in the bone marrow [1, 2]
Our present study has provided first evidence that AML cells synthesize ADAM17 and express it at their surface
Another major finding of our study is the striking downregulation of ADAM17 following CD13 ligation by anti-CD13 monoclonal antibodies (mAbs)
Summary
Acute myeloid leukaemia (AML) is a clinically and genetically heterogeneous haematopoietic cancer characterized by the clonal accumulation of immature myeloid precursors in the bone marrow [1, 2]. The secreted matrix metalloproteinases (MMPs) (including MMP-2 and MP9) and membrane-anchored ADAMs (a disintegrin and metalloproteinase) (including ADAM17, known as tumour necrosis factor-α-converting enzyme) cleave many different targets (ECM, cytokines, growth factors, chemokines and cytokine/growth factor receptors) [9,10,11,12] Through their proteolytic activities, these proteases are implicated in tumour-associated processes such as cell growth, survival, migration, invasion and angiogenesis [11, www.impactjournals.com/oncotarget. There is compelling evidence to suggest that by binding cell surface proteins, secreted MMP-2 and MMP9 can directly trigger intracellular signalling pathways that control tumour cell events [13] Another family of membrane-anchored enzymes (the ectopeptidases, including the metalloenzyme aminopeptidase-N/CD13) have been shown to participate in extracellular proteolysis and influence major biological processes (cell growth, motility and the secretion of inflammatory and angiogenic cytokines) [5, 14, 15]. We demonstrate that ADAM17 is expressed in primary AML cells, identified a novel CD13-ADAM17 interaction and provided evidence that CD13 ligation downregulates ADAM17 surface expression in AML
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