Abstract
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.
Highlights
Zoledronic acid (ZOL) is a third-generation bisphosphonate, commonly used for the treatment and prevention of osteoporosis [1] as well as for metastatic bone disease [2]
Bisphosphonates act in the mevalonate pathway by inhibiting farnesyl diphosphate synthase (FDPS) [3], which is required for the biosynthesis of cholesterol and as well as other isoprenoid lipids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)
The leukemic gene rearrangement MA9 was introduced into CBCD34þ cells by lentiviral transduction and the cells were cultured in myeloid proliferation conditions with the cytokine cocktail (SCF, FLT3-L and IL3)
Summary
Zoledronic acid (ZOL) is a third-generation bisphosphonate, commonly used for the treatment and prevention of osteoporosis [1] as well as for metastatic bone disease [2]. Bisphosphonates act in the mevalonate pathway by inhibiting farnesyl diphosphate synthase (FDPS) [3], which is required for the biosynthesis of cholesterol and as well as other isoprenoid lipids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These molecules are responsible for the prenylation of small GTPases (Ras, Rho, Rac) that, in turn, regulate osteoclast function and can be activated in leukemias and hematological malignancies [4]. The rational is that ZOL can block the key enzyme required for farnesylation needed for prenylation of the GTPases preventing association with the plasma membrane for Rac signaling
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