Integration of gene expression patterns, fusions, mutations, cytogenetics and other clinical variables for subtyping leukemias and targeting therapies

项目概要/摘要 最近发现的儿童急性白血病（ALL）的Ph样亚型代表了一个重大突破 对这种疾病的理解和管理。这一分组约占四分之一 在所有儿童高危ALL患者中，有一半以上的死亡是由它引起的。特征 Ph样患者的基因表达特征使其能够在诊断时被识别，并有助于在诊断中识别Ph样患者。 深入表征其获得性潜在分子异常，包括：基因融合， 酪氨酸激酶基因及其通路，CRLF 2的易位和缺失，JAK激酶的突变， IL 7 R的插入/缺失。虽然这些融合的发现仍在进行中，但许多这些激酶事件 已显示对酪氨酸激酶抑制剂（TKI）和其他靶向治疗有反应， 临床鉴定至关重要。 所提出的工作既是对类Ph情形的表征的继续，也是对类Ph情形的应用。 临床试验中的Ph样基因表达检测，以允许评估和开发靶向药物 治疗这些患者。这涉及对一个非常大的诊断性ALL前瞻性队列的初步检测 样本，以确定是否存在类似PH的签名。同时鉴定了类Ph 为了检测CRLF信号，还进行了最常见的CRLF 2融合的检测，以及确定CRLF信号的频率。 其他CRLF 2重排的可能性。其余的PH样病例（仅占约10-15%） 然后对初始队列）进行转录组测序（RNA-Seq），以快速鉴定 表达的融合、突变和相关的插入/缺失。这一阶段的工作将扩大发现 新的融合，也允许分配已知的融合靶向治疗。的组合 发现和表征这些具有完整基因表达信息的获得性事件也将允许新的 预测模型和分析方法有待开发。 在接下来的几年里，这项工作的高潮是将Ph样ALL患者从最严重的 结果组最好的。这方面的先例是BCR-ABL 1患者TKI治疗的出现。 在过去的十年里，这些患者已经从预后最差的群体发展到最好的群体之一。 结果，主要是由于适当的靶向药物的管理。挑战在于 ph样患者的基因融合的巨大多样性（目前超过100）和困难， 诊断和描述它们。基因表达分析及测序策略的应用 本提案中所描述的解决这两个问题，也允许有针对性的融合， 成为临床试验的一部分。

Project Summary/Abstract The recent discovery of the Ph-like subtype of childhood acute leukemia (ALL) represents a major breakthrough in the understanding and management of this disease. This subgroup accounts for approximately one quarter of all childhood high-risk ALL patients and is responsible for more than half of their deaths. The characteristic gene expression signature of the Ph-like patients allows them to be identified at diagnosis and facilitates an in depth characterization of their acquired underlying molecular abnormalities, including: gene fusions involving tyrosine kinase genes and their pathways, translocations and deletions of CRLF2, mutations of JAK kinases and insertions/deletions of IL7R. While the discovery of these fusions is still ongoing, many of these kinase events have been shown to be responsive to tyrosine kinase inhibitors (TKIs) and other targeted therapies, making their identification clinically crucial. The proposed work is both a continuation of the characterization of Ph-like cases and also the application of the Ph-like gene expression assay in clinical trials to permit the evaluation and development of targeted drug therapies for these patients. This involves the initial testing of a very large prospective cohort of diagnostic ALL samples to determine if the Ph-like signature is present. Simultaneously with the identification of the Ph-like signature, testing for the most common CRLF2 fusion is also performed as well as a determination of the likelihood of other CRLF2 rearrangements. The remaining Ph-like cases (comprising only about 10-15% of the initial cohort) will then be subjected to transcriptomic sequencing (RNA-Seq) for the rapid identification of expressed fusions, mutations and related insertions/deletions. This phase of the work will expand the discovery of new fusions and also permit the assignment of known fusions to targeted therapies. The combination of the discovery and characterization of these acquired events with full gene expression information will also allow new predictive models and assays to be developed. Within the next several years the culmination of this work is to transform the Ph-like ALL patients from the worst outcome group to the best. The precedent for this has been the advent of TKI therapy for BCR-ABL1 patients. Over the past ten years these patients have evolved from the poorest prognosis group to among the best outcomes, principally due to the administration of appropriate targeted drugs. The challenge in doing this with Ph-like patients has been the enormous diversity of gene fusions (currently more than 100) and the difficulty in diagnosing and characterizing them. The application of the gene expression assay and sequencing strategy described in this proposal address both of those issues and also allow for the targetable fusions to immediately become part of clinical trials.