Salas A.Ponnusamy S.Senkal C.E.Meyers-Needham M.Selvam S.P.Saddoughi S.A.Apohan E.2024-08-042024-08-0420110006-4971https://doi.org/10.1182/blood-2010-08-300772https://hdl.handle.net/11616/90358The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1-/- MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34+ mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance. © 2011 by The American Society of Hematology.eninfo:eu-repo/semantics/openAccess4 (2,6 dichloro 4 pyridinyl) 1 (1,3 dimethyl 4 isopropyl 1h pyrazolo[3,4 b]pyridin 6 yl)semicarbazideBCR ABL proteinBCR ABL1 proteinimatiniblactacystinnilotinibphosphoprotein phosphatase 2Asmall interfering RNAsphingosine 1 phosphate receptorsphingosine 1 phosphate receptor 2sphingosine kinase 1unclassified druganimal experimentarticlecancer cell culturecancer resistancecell growthchronic myeloid leukemiacontrolled studydrug mechanismdrug targetingenzyme activationhumanhuman cellmousenonhumanpriority journalprotein degradationprotein dephosphorylationprotein expressionprotein stabilitysignal transductiontherapy resistanceArticle11722594159522152751510.1182/blood-2010-08-3007722-s2.0-79957980683Q1