Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
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DOI：
10.1371/journal.pone.0121912
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mathews V
中科院分区：
文献类型：
--
作者：
Chendamarai E;Ganesan S;Alex AA;Kamath V;Nair SC;Nellickal AJ;Janet NB;Srivastava V;Lakshmi KM;Viswabandya A;Abraham A;Aiyaz M;Mullapudi N;Mugasimangalam R;Padua RA;Chomienne C;Chandy M;Srivastava A;George B;Balasubramanian P;Mathews V
与新诊断病例（NAPL）相比，复发急性早幼粒细胞白血病（RAPL）的临床、细胞和分子变化数据有限。我们进行了一项前瞻性研究，比较了使用三氧化二砷（ATO）治疗的NAPL和RAPL患者。98例NAPL和28例RAPL纳入本研究。RAPL患者在诊断时白细胞计数明显降低，血小板计数明显升高。RAPL组IC出血明显减少（P=0.022）。恶性早幼粒细胞在细胞内浓缩ATO的能力及其体外对ATO的IC50在两组间无显著差异。靶向NGS结果显示，RAPL亚群中有4例（15.38%）出现PML B2结构域突变，与ATO继发性耐药无关。微阵列GEP显示，1744个基因在两组之间差异表达2倍及以上。最显著的差异调节途径是细胞粘附（n=92）、细胞存活（n=50）、免疫调节（n=74）和干细胞调节（n=51）。与GEP数据一致，免疫表型分析显示RAPL病例中CD34表达显著增加（P=0.001），并且有体外证据表明微环境介导的ATO先天耐药（EM-DR）显著。ATO治疗后的耐药和复发可能是多因素的，仅在RAPL中发现的PML B2结构域突变可能不是随后复发的主要临床相关原因。在RAPL中，其他因素，如白血病起始室的扩大以及EM-DR，可能在ATO治疗后显著导致复发。
There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.
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