p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1α-mediated down-regulation of CXCL12
p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1α-mediated down-regulation of CXCL12
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DOI：
10.1182/blood-2011-02-334136
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发表时间：
2011-10-20
期刊：
影响因子：
20.3
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
--
作者：
Kojima, Kensuke;McQueen, Teresa;Andreeff, Michael
FMS样酪氨酸激酶-3（FLT 3）抑制剂已被用于克服FLT 3突变的急性髓性白血病（AML）的不良预后。FLT 3抑制剂单药治疗的临床结果表明，骨髓反应通常不如外周血反应明显。我们研究了骨髓基质细胞中p53在基质细胞介导的FLT 3突变AML对FLT 3抑制的抵抗中的作用。虽然FLT 3抑制剂FI-700在FLT 3突变AML细胞中诱导凋亡，但在基质共培养条件下凋亡诱导减少。保护似乎部分由CXCL 12（SDF-1）/CXCR 4信号传导介导。通过预先暴露于HDM 2抑制剂Nutlin-3a，基质细胞的保护作用显著降低。Nutlin-3a激活p53对基质细胞无细胞毒性，但部分通过p53介导的HIF-1 α下调降低CXCL 12 mRNA水平和CXCL 12分泌。结果显示，基质细胞中的p53活化减弱了基质细胞介导的对FLT 3抑制的抗性，部分是通过下调CXCL 12。这是首次报道Nutlin对骨髓环境的影响。我们认为，HDM 2拮抗剂和FLT 3抑制剂的组合可能是有效的针对突变型FLT 3白血病的临床试验。（血。2011; 118（16）：4431-4439）
Fms-like tyrosine kinase-3 (FLT3) inhibitors have been used to overcome the dismal prognosis of acute myeloid leukemia (AML) with FLT3 mutations. Clinical results with FLT3 inhibitor monotherapy have shown that bone marrow responses are commonly less pronounced than peripheral blood responses. We investigated the role of p53 in bone marrow stromal cells in stromal cell-mediated resistance to FLT3 inhibition in FLT3 mutant AML. While the FLT3 inhibitor FI-700 induced apoptosis in FLT3 mutant AML cells, apoptosis induction was diminished under stromal coculture conditions. Protection appeared to be mediated, in part, by CXCL12 (SDF-1)/CXCR4 signaling. The protective effect of stromal cells was significantly reduced by pre-exposure to the HDM2 inhibitor Nutlin-3a. p53 activation by Nutlin-3a was not cytotoxic to stromal cells, but reduced CXCL12 mRNA levels and secretion of CXCL12 partially through p53-mediated HIF-1 alpha down-regulation. Results show that p53 activation in stroma cells blunts stroma cell-mediated resistance to FLT3 inhibition, in part through down-regulation of CXCL12. This is the first report of Nutlin effect on the bone marrow environment. We suggest that combinations of HDM2 antagonists and FLT3 inhibitors may be effective in clinical trials targeting mutant FLT3 leukemias.(Blood. 2011; 118(16):4431-4439)