| 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
|
| リソース情報 |
| ヒト・動物細胞 |
HPB-ALL(RCB1935) |
