Scheijen Blanca, Boer Judith M, Marke René, Tijchon Esther, van Ingen Schenau Dorette, Waanders Esmé, van Emst Liesbeth, van der Meer Laurens T, Pieters Rob, Escherich Gabriele, Horstmann Martin A, Sonneveld Edwin, Venn Nicola, Sutton Rosemary, Dalla-Pozza Luciano, Kuiper Roland P, Hoogerbrugge Peter M, den Boer Monique L, van Leeuwen Frank N
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands.
Haematologica. 2017 Mar;102(3):541-551. doi: 10.3324/haematol.2016.153023. Epub 2016 Dec 15.
Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of were significantly enriched in -deleted B-cell precursor acute lymphoblastic leukemia (=0.007). While deletions alone had no impact on prognosis, the combined presence of and deletions was associated with a significantly lower 5-year event-free survival (=0.0003) and a higher 5-year cumulative incidence of relapse (=0.005), when compared with -deleted cases without aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as or , did not affect the outcome of -deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, -deficient mice were crossed onto an heterozygous background. We observed that loss of increased the tumor incidence of mice in a dose-dependent manner. Moreover, murine B cells deficient for and displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in -deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.
影响淋巴样转录因子IKZF1（IKAROS）的缺失和突变与B细胞前体急性淋巴细胞白血病的复发风险增加及预后不良相关。然而，其他遗传事件可能增强或抵消缺失对预后的影响。在一个由533例儿童B细胞前体急性淋巴细胞白血病患者组成的大型发现队列中，我们观察到在IKZF1缺失的B细胞前体急性淋巴细胞白血病中，BTG1单拷贝缺失显著富集（P = 0.007）。虽然单独的IKZF1缺失对预后没有影响，但与无BTG1异常的IKZF1缺失病例相比，IKZF1和BTG1联合缺失与显著更低的5年无事件生存率（P = 0.0003）及更高的5年累积复发率（P = 0.005）相关。相反，在B细胞前体急性淋巴细胞白血病中常见的其他拷贝数缺失，如CDKN2A或RB1缺失，并不影响IKZF1缺失的急性淋巴细胞白血病患者的预后。为确定IKZF1和BTG1功能的联合缺失是否在白血病发生过程中协同作用，将BTG1缺陷小鼠与IKZF1杂合背景小鼠杂交。我们观察到BTG1缺失以剂量依赖方式增加了IKZF1小鼠的肿瘤发生率。此外，同时缺乏IKZF1和BTG1的小鼠B细胞对糖皮质激素的抗性增加，但对其他化疗药物无抗性。总之，我们的结果确定BTG1为白血病中的肿瘤抑制因子，其缺失时会强烈增加IKZF1缺失的B细胞前体急性淋巴细胞白血病的复发风险，并增强由IKZF1功能缺失介导的糖皮质激素抗性表型。
