Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia
Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia
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DOI：
10.1182/blood-2012-01-407601
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发表时间：
2012-09-06
期刊：
影响因子：
20.3
通讯作者：
Stock, Wendy
中科院分区：
文献类型：
--
作者：
Gallagher, Robert E.;Moser, Barry K.;Stock, Wendy
全反式维甲酸(ATRA)靶向的PML-RARα配体结合域(PRα/LBD+)突变参与了对ATRA耐药的急性早幼粒细胞白血病克隆的被动选择，导致疾病复发。在组间方案C9710的ATRA/化疗组的45例复发患者中，18例PRα/LBD+(40%)，其中7例(39%)复发超出ATRA选择压力，提示PRα/LBD+可能起积极作用。在共分析的41例复发患者中，15例(37%)有FMS相关的酪氨酸激酶3内部串联重复突变(Flt3-ITD+)，其与PRα/LBD+的相关性取决于复发时ATRA的治疗状态：阳性，在ATRA上；阴性，在ATRA下。21例患者中有13例(62%)有额外的染色体异常(ACA)；所有共同分析的PRα/LBD突变患者(n=5)复发的非ATRA患者都与ACA相关。复发后ACA与Flt3-ITD+呈负相关，与白细胞计数和PML-RARα呈负相关：ACA、Low、L亚型；Flt3-ITd+、HIGH、S亚型。这些探索性结果表明，不同的PRα/LBD+活性可能与Flt3-ITD+或ACA相互作用，Flt3-ITD+和ACA与复发时表现出的不同内在疾病进展途径有关，这些不同的途径可能被复发时ATRA可选择的缺陷所短路。ACA和某些PRα/LBD+也与复发后生存率降低有关。(血。2012；120(10)：2098-2108)
Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RAR alpha (PR alpha/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PR alpha/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PR alpha/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PR alpha/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PR alpha/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RAR alpha type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PR alpha/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PR alpha/LBD+ were also associated with reduced postrelapse survival. (Blood. 2012; 120(10):2098-2108)