Abstract
Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells. NOX-A12 was sufficient to suppress SDF-1-induced migration in vitro. The combination of NOX-A12 with TKIs reduced cell migration in the same in vitro model of SDF-1-induced chemotaxis to a greater extent than either drug alone, suggesting positive cooperativity as a result of the SDF-1 blocking function of NOX-A12 and cytotoxicity resulting from targeted oncogenic kinase inhibition. These results are consistent with our in vivo findings using a functional pre-clinical mouse model of chronic myeloid leukemia (CML), whereby we demonstrated the ability of NOX-A12, combined with the ABL kinase inhibitor, nilotinib, to reduce the leukemia burden in mice to a greater extent than either agent alone. Overall, the data support the idea of using SDF-1 inhibition in combination with targeted kinase inhibition to override drug resistance in oncogene-driven leukemia to significantly diminish or eradicate residual leukemic disease.
Highlights
chronic myeloid leukemia (CML) is a malignancy of hematopoietic stem cells caused by the t(9;22) chromosome translocation product BCR-ABL [1]
In transwell migration assays designed to test the ability of NOX-A12 to inhibit SDF-1-induced migration of BCR-ABL-expressing cells, we found that 50–100 nM NOX-A12 effectively inhibited the SDF-1-stimulated migration of BCR-ABL-expressing Ba/F3 and 32D cells and reduced migration to a level similar to unstimulated control cells (Figure 1A, 1D and Supplementary Figure 1A)
We showed in a separate set of studies performed in parallel that 19 hours of stimulation of Ba/F3.p210 cells with SDF-1 led to a strong induction of cell migration in a transwell migration assay, whereas 19 hours of SDF-1 stimulation of Ba/F3.p210 cells did not lead to any measurable increase in cell proliferation (Supplementary Figure 1B–1C)
Summary
CML is a malignancy of hematopoietic stem cells caused by the t(9;22) chromosome translocation product BCR-ABL [1]. Excessive proliferation and abnormal trafficking of transformed progenitor cells provides a survival advantage that is accompanied by premature release of these cells into the bloodstream of patients. This has been partially attributed to BCR-ABL-altered integrin expression or function affecting the communication between leukemic cells and the bone marrow stroma, as well as with important extracellular matrix proteins such as fibronectin [2,3,4,5,6]. In one study, CML recurred in more than 50% of patients who discontinued imatinib therapy after having achieved and maintained at least a www.impactjournals.com/oncotarget
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