Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
复制标题
DOI：
10.1038/ng.3362
复制
发表时间：
2015-09
期刊：
影响因子：
30.8
通讯作者：
Yaspo ML
中科院分区：
文献类型：
--
作者：
Fischer U;Forster M;Rinaldi A;Risch T;Sungalee S;Warnatz HJ;Bornhauser B;Gombert M;Kratsch C;Stütz AM;Sultan M;Tchinda J;Worth CL;Amstislavskiy V;Badarinarayan N;Baruchel A;Bartram T;Basso G;Canpolat C;Cario G;Cavé H;Dakaj D;Delorenzi M;Dobay MP;Eckert C;Ellinghaus E;Eugster S;Frismantas V;Ginzel S;Haas OA;Heidenreich O;Hemmrich-Stanisak G;Hezaveh K;Höll JI;Hornhardt S;Husemann P;Kachroo P;Kratz CP;Te Kronnie G;Marovca B;Niggli F;McHardy AC;Moorman AV;Panzer-Grümayer R;Petersen BS;Raeder B;Ralser M;Rosenstiel P;Schäfer D;Schrappe M;Schreiber S;Schütte M;Stade B;Thiele R;von der Weid N;Vora A;Zaliova M;Zhang L;Zichner T;Zimmermann M;Lehrach H;Borkhardt A;Bourquin JP;Franke A;Korbel JO;Stanulla M;Yaspo ML
TCF 3-HLF融合阳性急性淋巴细胞白血病（ALL）目前无法治愈。采用综合方法，我们发现了TCF 3-HLF阳性和治疗反应性TCF 3-PBX 1阳性ALL中不同的突变、基因表达和药物反应特征。在TCF 3-HLF的星座中鉴定了PAX 5或VPREB 1的复发性基因内缺失。此外，TCF 3非易位等位基因的体细胞突变和TCF 3-HLF ALL中PAX 5基因剂量的减少表明在有限的遗传背景下的合作。在TCF 3-HLF标签中富集干细胞和髓样特征可能反映了TCF 3-HLF将起源的淋巴定向细胞重编程为杂合的耐药性造血状态。匹配的患者来源的异种移植物的药物反应分析显示，TCF 3-HLF ALL具有独特的特征，对传统化疗药物具有耐药性，但对糖皮质激素、蒽环类药物和临床开发药物敏感。使用BCL 2特异性抑制剂venetoclax（ABT-199）实现了对靶敏感性的打击。因此，这种综合方法为这种致命疾病提供了替代治疗方案。
TCF3-HLF-fusion positive acute lymphoblastic leukemia (ALL) is currently incurable. Employing an integrated approach, we uncovered distinct mutation, gene expression, and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. Recurrent intragenic deletions of PAX5 or VPREB1 were identified in constellation with TCF3-HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin towards a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics, but sensitivity towards glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.