新遗传标志物可作为白血病治疗靶点

SAN DIEGO (EGMN) – Novel genetic alterations have been identified in a new subtype of high-risk B-cell acute lymphoblastic leukemia that could be effectively targeted with existing therapies.

The subtype, termed Ph-like ALL, was first identified by the Children’s Oncology Group in 2009 (N. Engl. J. Med. 2009;360:470-80), and accounts for up to 15% of pediatric acute lymphoblastic leukemia (ALL) cases.

“Until this study, the genetic basis of Ph-like ALL was unknown,” said Kathryn G. Roberts, Ph.D., lead author of the cooperative research study.

Ph-like ALL is associated with alteration of lymphoid transcription factors, most commonly IKZF1, and has a gene expression profile similar to that of Philadelphia chromosome–positive (Ph+) ALL. Ph+ ALL accounts for just 5% of pediatric ALL cases, but because it is driven by the oncogenic tyrosine kinase, BCR-ABL1, it can be effectively treated with available tyrosine kinase inhibitors such as imatinib.

Ph-like ALL, however, is BCR-ABL negative, so patients with this poor-outcome subtype are currently treated with conventional chemotherapy. Higher doses and intensified regimens are limited by toxicity.

Screening ALL patients at the time of diagnosis could identify those with Ph-like ALL, and determine who may benefit from more-aggressive treatment with targeted therapies, said Dr. Roberts, a postdoctoral pathology fellow at St. Jude Children’s Research Hospital in Memphis, Tenn.

In an effort to better understand the genetic basis of Ph-like ALL, the investigators used next-generation genome sequencing and other techniques to analyze the transcriptome or RNA sequence of 12 patients with Ph-like ALL. Strikingly, 11 of the 12 cases harbored alterations disrupting kinase and cytokine receptor signaling, which provides a treatable target with current drugs, she said. The alterations included novel rearrangements, structural variations, and sequence mutations.

Specifically, the spectrum of alterations included NUP214-ABL1 or RANBP2-ABL1 rearrangements, immunoglobulin heavy chain rearrangements involving the cytokine receptor genes CRLF2 and EPOR, and in-frame fusions of EBF1-PDGFRB (platelet-derived growth factor receptor beta), BCR-JAK2 or STRN3-JAK2. In addition, activating mutations within IL7R, and loss of function SH2B3 deletions were also identified.

Importantly, laboratory studies showed that patient samples harboring the ABL1 rearrangement were sensitive to the tyrosine kinase inhibitors imatinib, dasatinib, and XL228, whereas the JAK2-rearranged samples were sensitive to the JAK2 inhibitors XL019 and ruxolitinib, which was recently approved for the treatment of myelofibrosis. Furthermore, mouse cells harboring the EBF1-PDGFRB fusion responded to imatinib, dasatinib, and dovitinib, a specific PDGFRB/FGFR (fibroblast growth factor receptor) inhibitor, Dr. Roberts reported.

The group also screened 231 additional high-risk ALL patients (aged 1 year 2 months to 17 years 6 months) and found that the genetic alterations were present in 40 cases (17%), suggesting that these genetic lesions are “hallmarks of this subtype of ALL,” she said.

The diversity of lesions in Ph-like ALL suggests that screening methods to identify patients at diagnosis may be more attractive than transcriptome sequencing, Dr. Roberts noted. Phosphoflow cytometric signaling analysis can be used to detect activation of pathways common to the novel genetic lesions and to identify patients who will most likely respond to targeted therapy. Gene expression profiling is also being investigated as a complimentary approach to identify Ph-like ALL patients.

St. Jude is currently not screening its ALL patients for Ph-like ALL, but the researchers hope to be able to start treating children who have ALL based on their genetic alterations in the next 12 months, she said in an interview.

The researchers are also currently establishing Ph-like ALL animal models and plan to broaden the scope of their testing to include young adolescents and adults. The current study earned the outstanding abstract achievement award for a postdoctoral fellow at the meeting.

Click here to view a video interview with Dr. Roberts.

Dr. Roberts reported no conflicts of interest. A coauthor, Dr. Steve Hunger, reported that his children own stock in Bristol-Myers Squibb and that he is a member of an entity’s board of directors or advisory committee.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

圣迭戈(EGMN)——美国研究者在高危B细胞急性淋巴母细胞白血病(Ph样ALL)新亚型患者中发现了新的遗传学变异，后者可作为现有治疗的有效靶点。

为了明确Ph样ALL的遗传基础，圣犹大儿童研究医院的Kathryn G. Roberts博士及其同事采用新一代基因组测序等技术分析了12例Ph样ALL患者的转录组或RNA序列。值得注意的是，其中11例患者存在破坏激酶和细胞因子受体信号的变异。这些变异包括新的重排、结构变化和序列突变，可作为现有药物的治疗靶点。

具体而言，变异谱包括NUP214- ABL1或RANBP2- ABL1重排；涉及细胞因子受体基因CRLF2和EPOR的免疫球蛋白重链重排；以及EBF1 PDGFRB(血小板衍生生长因子受体β)、BCR-JAK2或STRN3-JAK2的框内融合。此外，研究者还检测到IL7R内的活化突变和功能SH2B3删除的缺失。

实验室检查发现，存在ABL1重排的患者样本对酪氨酸激酶抑制剂伊马替尼、达沙替尼和XL228敏感，而JAK2重排样本则对JAK2抑制剂XL019和ruxolitinib敏感。ruxolitinib最近刚被批准用于治疗骨髓纤维化。此外，存在EBF1-PDGFRB融合的小鼠细胞对伊马替尼、达沙替尼和dovitinib产生应答。dovitinib是一种特异性PDGFRB/FGFR(成纤维细胞生长因子受体)抑制剂。

研究者还筛查了另外231例高危ALL患者(年龄为1岁2个月~17岁6个月)，结果发现40例(17%)患者存在上述遗传学变异，表明这些遗传学变异是此亚型ALL的标志物。

由于Ph样ALL患者的病变存在多样性，因此诊断时的筛查方法比转录组测序可能更有用。Phosphoflow流式细胞仪信号分析可用于检测新遗传病变的共同通路的活化情况，并确定最有可能受益于靶向治疗的患者。目前，基因表达谱也正被研究作为检测Ph样ALL患者的辅助方法。研究者计划在未来1年根据遗传学变异来治疗罹患ALL的儿童患者。

Roberts博士声明无经济利益冲突。另一位研究者Steve Hunger博士声明其子女拥有百时美施贵宝公司的股份，并且自己是某公司董事会或咨询委员会的成员。

爱思唯尔  版权所有