title: The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling.
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.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Dorian
authors.initials: D
authors.lastname: Forte
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Salvestrini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Corradi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Rossi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Catani
authors.affiliation: Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Curti
mesh_terms: D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D060149:Tetraspanin 30 / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C554586:CD63 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C560822:TIMP1 protein, human; D060149:Tetraspanin 30; D019715:Tissue Inhibitor of Metalloproteinase-1; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
keywords: TIMP-1; acute myeloid leukemia; inflammation; microenvironment; migration