Research Papers:

The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

Dorian Forte _, Valentina Salvestrini, Giulia Corradi, Lara Rossi, Lucia Catani, Roberto M. Lemoli, Michele Cavo and Antonio Curti

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Oncotarget. 2017; 8:2261-2274. https://doi.org/10.18632/oncotarget.13664

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Dorian Forte1, Valentina Salvestrini1, Giulia Corradi1, Lara Rossi1, Lucia Catani1, Roberto M. Lemoli2, Michele Cavo1, Antonio Curti1

1Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, Bologna, Italy

2Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy

Correspondence to:

Dorian Forte, email: [email protected]

Keywords: acute myeloid leukemia, inflammation, microenvironment, migration, TIMP-1

Received: April 11, 2016     Accepted: November 21, 2016     Published: November 26, 2016


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.

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