Abstract
We and others have shown that the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), a member of the inflammatory network exerting pleiotropic effects in the bone marrow (BM) microenvironment, regulates the survival and proliferation of different cell types, including normal hematopoietic progenitor cells. Moreover, TIMP-1 has been shown to be involved in cancer progression. However, its role in leukemic microenvironment has not been addressed. Here, we investigated the activity of TIMP-1 on Acute Myelogenous Leukemia (AML) cell functions. First, we found that TIMP-1 levels were increased in the BM plasma of AML patients at diagnosis. In vitro, recombinant human (rh)TIMP-1 promoted the survival and cell cycle S-phase entry of AML cells. These kinetic effects were related to the downregulation of cyclin-dependent kinase inhibitor p21. rhTIMP-1 increases CXCL12-driven migration of leukemic cells through PI3K signaling. Interestingly, activation of CD63 receptor was required for TIMP-1's cytokine/chemokine activity. Of note, rhTIMP-1 stimulation modulated mRNA expression of Hypoxia Inducible Factor (HIF)-1α, downstream of PI3K/Akt activation. We then co-cultured AML cells with normal or leukemic mesenchymal stromal cells (MSCs) to investigate the interaction of TIMP-1 with cellular component(s) of BM microenvironment. Our results showed that the proliferation and migration of leukemic cells were greatly enhanced by rhTIMP-1 in presence of AML-MSCs as compared to normal MSCs. Thus, we demonstrated that TIMP-1 modulates leukemic blasts survival, migration and function via CD63/PI3K/Akt/p21 signaling. As a “bad actor” in a “bad soil”, we propose TIMP-1 as a potential novel therapeutic target in leukemic BM microenvironment.
Highlights
Acute Myelogenous Leukemia (AML) is a clonal disorder which originates from a rare population of leukemia stem cells (LSCs) [1]
We demonstrate that Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) increases the clonogenic efficiency, the survival and the migratory capacity of AML blasts by binding to CD63 receptor which, in turn, results in the activation of PI3K, Akt phosphorylation and regulation of downstream targets, such as p21 and Hypoxia Inducible Factor (HIF)-1α
We showed the potential role of TIMP-1 in the interplay between leukemic blasts and AML mesenchymal stromal cells (MSCs)
Summary
Acute Myelogenous Leukemia (AML) is a clonal disorder which originates from a rare population of leukemia stem cells (LSCs) [1]. Recent reports have unveiled a pathogenetic link between inflammation and oncogenesis [4,5,6,7]. Whereas this finding is well-accepted for solid tumors, the relationship between inflammatory networks and leukemogenesis has not been fully elucidated. Recent data highlight how hematopoietic stem progenitor cells (HSPCs) fate is dictated by intrinsic and extrinsic factors and how HSPCs may actively sense danger signals and pro-inflammatory cytokines [8,9,10]. Several factors and pathways have been implicated and described [11, 12]
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