Reshmi Shalini C, Harvey Richard C, Roberts Kathryn G, Stonerock Eileen, Smith Amy, Jenkins Heather, Chen I-Ming, Valentine Marc, Liu Yu, Li Yongjin, Shao Ying, Easton John, Payne-Turner Debbie, Gu Zhaohui, Tran Thai Hoa, Nguyen Jonathan V, Devidas Meenakshi, Dai Yunfeng, Heerema Nyla A, Carroll Andrew J, Raetz Elizabeth A, Borowitz Michael J, Wood Brent L, Angiolillo Anne L, Burke Michael J, Salzer Wanda L, Zweidler-McKay Patrick A, Rabin Karen R, Carroll William L, Zhang Jinghui, Loh Mignon L, Mullighan Charles G, Willman Cheryl L, Gastier-Foster Julie M, Hunger Stephen P
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH.
Department of Pathology, The Ohio State University College of Medicine, Columbus, OH.
Blood. 2017 Jun 22;129(25):3352-3361. doi: 10.1182/blood-2016-12-758979. Epub 2017 Apr 13.
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of - (n = 46) or - (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of (- or -) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (, , ) identified in 63 patients (50.8% of those with rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (, , , and ) in 14.1%, rearrangements or fusions in 8.8%, alterations activating other JAK-STAT signaling genes (, , ) in 6.3% or other kinases (, , ) in 4.6%, and mutations involving the Ras pathway (, , , ) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.
费城染色体样（Ph样）急性淋巴细胞白血病（ALL）是一种高危亚型，其特征为激活细胞因子受体和激酶信号传导的基因组改变。我们在一个回顾性队列中研究了1389例连续诊断的具有高危临床特征和/或在缓解诱导治疗结束时微小残留病升高的儿童B系ALL患者中可靶向遗传病变的频率和谱。在1389例患者中的341例中鉴定出Ph样基因表达谱，其中57例因存在-（n = 46）或-（n = 11）而被排除在进一步分析之外。在其余284例患者（20.4%）中，124例（43.7%）鉴定出（-或-）的过表达和重排，63例患者（重排患者中的50.8%）鉴定出伴随激活JAK-STAT途径的基因组改变（，，）。在其余患者中，使用逆转录酶聚合酶链反应或转录组测序，我们在14.1%的患者中鉴定出可靶向的ABL类融合（，，，和），在8.8%的患者中鉴定出重排或融合，在6.3%的患者中鉴定出激活其他JAK-STAT信号基因（，，）或在4.6%的患者中鉴定出其他激酶（，，）的改变，以及在Ph样ALL患者中的6%鉴定出涉及Ras途径的突变（，，，）。我们为先前报道在Ph样ALL中重排的4个激酶基因鉴定出8个新的重排伙伴。目前的研究结果为儿童肿瘤学组ALL试验中实施的Ph样ALL的精准医学检测和治疗方法提供了支持。
