Zoledronic acid inhibits the growth of leukemic MLL-AF9 transformed hematopoietic cells
Emanuela Chiarella,
Bruna Codispoti,
Annamaria Aloisio,
Emanuela G. Cosentino,
Stefania Scicchitano,
Ylenia Montalcini,
Daniela Lico,
Giovanni Morrone,
Maria Mesuraca,
Heather M. Bond
Affiliations
Emanuela Chiarella
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
Bruna Codispoti
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; Tecnologica Research Institute-Marrelli Health, 88900 Crotone, Italy
Annamaria Aloisio
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
Emanuela G. Cosentino
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; Exiris S.r.l., 00128 Roma, Italy
Stefania Scicchitano
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
Ylenia Montalcini
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
Daniela Lico
Department of Obstetrics & Ginecology, University Magna Græcia, 88100 Catanzaro, Italy
Giovanni Morrone
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
Maria Mesuraca
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; Corresponding author.
Heather M. Bond
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; Corresponding author.
A leukemic in vitro model produced by transducing Cord Blood derived-hematopoietic CD34+ cells with the MLL-AF9 translocation resulting in the oncogenic fusion protein, is used to assess for sensitivity to Zoledronic acid. These cells are practically immortalized and are of myeloid origin. Proliferation, clonogenic and stromal co-culture assays showed that the MLL-AF9 cells were considerably more sensitive to Zoledronic acid than normal hematopoietic CD34+ cells or MS-5 stromal cells. The MLL-AF9 cells were notably more inhibited by Zoledronic acid when cultured as colonies in 3 dimensions, requiring cell-cell contacts compared to suspension expansion cultures. This is coherent with the mechanism of action of Zoledronic acid inhibiting farnesyl diphosphate synthase which results in a block in prenylation of GTPases such that their role in the membrane is compromised for cell-cell contacts. Zoledronic acid can be proposed to target the MLL-AF9 leukemic stem cells before they emerge from the hematopoietic niche, which being in proximity to bone osteoclasts where Zoledronic acid is sequestered can be predicted to result in sufficient levels to result in an anti-leukemic action.
