CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model

被引：0
作者：
Y Zhang
S Patel
H Abdelouahab
M Wittner
C Willekens
S Shen
A Betems
V Joulin
P Opolon
O Bawa
F Pasquier
M Ito
N Fujii
P Gonin
E Solary
W Vainchenker
P Coppo
S De Botton
F Louache
机构：
[1] Institut National de la Santé et de la Recherche Médicale (INSERM),Laboratory Animal Research Department
[2] U1009,Département d’Hématologie
[3] 114 rue Edouard Vaillant,Département d’Hématologie
[4] 94805 Villejuif,undefined
[5] France,undefined
[6] Université Paris Sud,undefined
[7] 114 rue Edouard Vaillant,undefined
[8] 94805 Villejuif,undefined
[9] France,undefined
[10] Institut Gustave Roussy,undefined
[11] IFR54,undefined
[12] 114 rue Edouard Vaillant,undefined
[13] 94805 Villejuif,undefined
[14] France,undefined
[15] Université Paris VII,undefined
[16] 5 Rue Thomas Mann,undefined
[17] 75013 Paris,undefined
[18] France,undefined
[19] INSERM,undefined
[20] U848,undefined
[21] 114 rue Edouard Vaillant,undefined
[22] 94805 Villejuif,undefined
[23] France,undefined
[24] Institut Gustave Roussy,undefined
[25] IRCIV,undefined
[26] Laboratoire de Pathologie Experimentale,undefined
[27] 114 Edouard Vaillant,undefined
[28] 94805 Villejuif,undefined
[29] France,undefined
[30] Central Institute for Experimental Animals,undefined
[31] Kyoto University,undefined
[32] Graduate School of Pharmaceutical Sciences,undefined
[33] Institut Gustave Roussy,undefined
[34] IRCIV,undefined
[35] Plateforme d’Evaluation Préclinique,undefined
[36] 114 Edouard Vaillant,undefined
[37] 94805 Villejuif,undefined
[38] France,undefined
[39] 184 Rue du Faubourg Saint-Antoine,undefined
[40] 75012 Paris,undefined
[41] France,undefined
[42] Université Paris VI,undefined
[43] 4 Place Jussieu,undefined
[44] 75005 Paris,undefined
[45] France,undefined
[46] Institut Gustave Roussy,undefined
[47] 114 rue Edouard Vaillant,undefined
[48] 94805 Villejuif,undefined
[49] France,undefined
[50] Institut National de la Santé et de la Recherche Médicale (INSERM),undefined
来源：
Cell Death & Disease | 2012年 / 3卷
关键词：
CXCR4; CXCL12; acute myeloid leukemia; niche; leukemia-initiating cells; inhibitors;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4high from CXCR4neg/low AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rγnull (NOG) leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs.
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页码：e396 / e396
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