Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia.
Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia.
复制标题
DOI：
10.1016/j.exphem.2016.04.011
复制
发表时间：
2016-07
影响因子：
2.6
通讯作者：
Ley TJ
中科院分区：
文献类型：
--
作者：
Griffith M;Griffith OL;Krysiak K;Skidmore ZL;Christopher MJ;Klco JM;Ramu A;Lamprecht TL;Wagner AH;Campbell KM;Lesurf R;Hundal J;Zhang J;Spies NC;Ainscough BJ;Larson DE;Heath SE;Fronick C;O'Laughlin S;Fulton RS;Magrini V;McGrath S;Smith SM;Miller CA;Maher CA;Payton JE;Walker JR;Eldred JM;Walter MJ;Link DC;Graubert TA;Westervelt P;Kulkarni S;DiPersio JF;Mardis ER;Wilson RK;Ley TJ
复发性成人B淋巴细胞白血病（B- all）发病机制的基因组事件尚不清楚。我们对一名原发B-ALL患者的9个时间点的全基因组、外显子组、定制捕获、RNA-seq和位点特异性基因组分析进行了综合分析。全面的基因组和转录组特征揭示了肿瘤在进展过程中的戏剧性进化，在第二次复发时产生具有复杂克隆结构的肿瘤。我们观察并验证了EP300和NF1的点突变、高表达的EP300- znf384基因融合、IKZF1的微缺失、影响SETD2的局灶性缺失以及影响RB1、PAX5、NF1和ETV6的大缺失。虽然基因组分析揭示了潜在的生物学相关性事件，但在第二次复发时没有明显的临床可操作的治疗方案。然而，转录组分析发现FLT3基因编码的靶蛋白激酶异常过表达。尽管患者在补救性治疗后出现了第二次复发，但使用FLT3抑制剂舒尼替尼治疗迅速诱导了近乎完全的分子反应，允许患者进行匹配的非亲属供体干细胞移植。4年多后，患者仍处于完全缓解状态。对该患者复发基因组的分析揭示了一个意想不到的、可操作的治疗靶点，导致了与快速临床反应相关的特定治疗。对于一些复发或难治性癌症患者，这种方法可能表明新的治疗干预措施可以改变患者的预后。
The genomic events responsible for the pathogenesis of relapsed adult B lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole genome, exome, custom capture, RNA-seq, and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. While the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched unrelated donor stem cell transplant. The patient remains in complete remission more than 4 years later. Analysis of this patient’s relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate novel therapeutic interventions that could alter patient outcomes.