論文 - 詳細
| RRC ID | 51701 |
|---|---|
| 著者 | Randhawa S, Cho BS, Ghosh D, Sivina M, Koehrer S, Müschen M, Peled A, Davis RE, Konopleva M, Burger JA. |
| タイトル | Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B-cell acute lymphoblastic leukaemia. |
| ジャーナル | Br J Haematol |
| Abstract |
B cell acute lymphoblastic leukaemia (B-ALL) cells express high levels of CXCR4 chemokine receptors for homing and retention within the marrow microenvironment. Bone marrow stromal cells (BMSC) secrete CXCL12, the ligand for CXCR4, and protect B-ALL cells from cytotoxic drugs. Therefore, the therapeutic use of CXCR4 antagonists has been proposed to disrupt cross talk between B-ALL cells and the protective stroma. Because CXCR4 antagonists can have activating agonistic function, we compared the genetic and pharmacological deletion of CXCR4 in B-ALL cells, using CRISPR-Cas9 gene editing and CXCR4 antagonists that are in clinical use (plerixafor, BKT140). Both genetic and pharmacological CXCR4 inhibition significantly reduced B-ALL cell migration to CXCL12 gradients and beneath BMSC, and restored drug sensitivity to dexamethasone, vincristine and cyclophosphamide. NOD/SCID/IL-2rγnull mice injected with CXCR4 gene-deleted B-ALL cells had significant delay in disease progression and superior survival when compared to control mice injected with CXCR4 wild-type B-ALL cells. These findings indicate that anti-leukaemia activity of CXCR4 antagonists is primarily due to CXCR4 inhibition, rather than agonistic activity, and corroborate that CXCR4 is an important target to overcome stroma-mediated drug resistance in B-ALL. |
| 巻・号 | 174(3) |
| ページ | 425-36 |
| 公開日 | 2016-8-1 |
| DOI | 10.1111/bjh.14075 |
| PMID | 27071778 |
| PMC | PMC4959949 |
| MeSH | Animals Cell Line Cell Movement / drug effects Chemokine CXCL12 / metabolism Drug Resistance / drug effects Gene Editing Humans Leukemia, B-Cell / metabolism Leukemia, B-Cell / pathology Mice Mice, Inbred Strains Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology* Receptor Cross-Talk / drug effects Receptors, CXCR4 / antagonists & inhibitors* Receptors, CXCR4 / genetics Stromal Cells / metabolism Tumor Cells, Cultured |
| IF | 5.518 |
| 引用数 | 12 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HPB-ALL(RCB1935) |