Analysis of factors that affect in vitro chemosensitivity of leukaemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukaemia
Analysis of factors that affect in vitro chemosensitivity of leukaemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukaemia
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DOI：
10.1038/leu.2009.199
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发表时间：
2010-01-01
期刊：
影响因子：
11.4
通讯作者：
Pallis, M.
中科院分区：
文献类型：
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作者：
Jawad, M.;Seedhouse, C.;Pallis, M.
急性髓系白血病(AML)的复发被认为是由于耐药白血病干细胞和祖细胞(LSPC)在骨髓的利基微环境中持续存在所致。识别有可能在利基微环境中靶向这些LSPC的新型药物将有助于确定缓解后化疗的候选药物的特征。利用体外模型，我们发现吉珠单抗(Mylotarg)培养48h后，CD34(+)CD38(-)CD123(+)LSPC数量减少了34%，而正常CD34(+)CD38(-)造血干细胞对该药物不敏感。由于LSPC对Mylotarg治疗的反应有相当大的异质性，因此评估了可能支持差异反应的各种因素。高表达CD33者(P=0.008)、P-糖蛋白阴性者(P=0.008)、Flt3基因内部串联重复状态(Flt3/ITD)者(P=0.006)对Mylotarg治疗效果较好。与所有其他病例相比，具有这些组合特征和低负荷的患者样本的LSPC对Mylotarg的化疗敏感性显著增加(P=0.002)。在多因素分析中，LSPC负荷和Flt3状态是LSPC对Mylotarg化疗敏感性的预测因素(P
Relapse in acute myeloid leukaemia (AML) is considered to result from the persistence of drug-resistant leukaemic stem and progenitor cells (LSPC) within a bone marrow 'niche' microenvironment. Identifying novel agents that have the potential to target these LSPC in their niche microenvironment will aid in the characterization of candidate agents for postremission chemotherapy. Using an in vitro model, we found that 48-h culture with gemtuzumab ozogamicin (Mylotarg) resulted in a 34% reduction in CD34(+)CD38(-) CD123(+) LSPC number, whereas normal CD34(+)CD38(-) haemapoietic stem cells were insensitive to this agent. As there was considerable heterogeneity in LSPC response to Mylotarg treatment, various factors potentially underpinning the differential response were assessed. LSPC that overexpressed CD33 (P = 0.01), which were P-glycoprotein-negative (P = 0.008) and with internal tandem duplication (ITD) of the FLT3 gene (FLT3/ITD) status (P = 0.006) responded better to Mylotarg treatment. LSPC from patient samples that have these combined characteristics as well as low LSPC burden showed significantly more chemosensitivity to Mylotarg compared with all other cases (P = 0.002). In multivariate analysis, LSPC burden and FLT3 status were found to be predictors of LSPC chemosensitivity to Mylotarg treatment (P