Tasian Sarah K, Loh Mignon L
Department of Pediatrics, Division of Pediatric Hemotology-Oncology, University of California San Francisco, San Francisco, CA 94143, USA.
Crit Rev Oncog. 2011;16(1-2):13-24. doi: 10.1615/critrevoncog.v16.i1-2.30.
Recent genomic analyses of childhood and adult B-precursor acute lymphoblastic leukemia (ALL) samples have identified novel genetic alterations in essential lymphoid development and signal transduction pathways, providing insight into the pathogenesis of high-risk ALL associated with treatment failure. Particular advances have been made in unraveling the genetics of ALL associated with overexpression of the cytokine receptor-like factor 2 gene (CRLF2), which is frequently accompanied by simultaneous activating mutations in genes encoding Ikaros (IKZF1), Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), and/or the IL-7 receptor alpha chain (IL7RA). Children and adults with high-risk CRLF2-overexpressing ALL have high rates of relapse and dismal overall survival. Various groups have thus attempted to characterize the biochemical consequences of these genetic lesions via preclinical models with the goal of identifying targets for new therapies. These studies provide early data suggesting the promise of signal transduction inhibitors (STIs) of the JAK/STAT and PI3K pathways for CRLF2-overexpressing ALL. Additional research efforts continue to elucidate these aberrant signaling networks to provide rationale for bringing STIs into the clinic for these high-risk patients. This review highlights the current knowledge of the incidence, prognostic significance, and biology of CRLF2-overexpressing ALL and future directions for development of targeted therapies.
近期对儿童和成人B前体急性淋巴细胞白血病（ALL）样本的基因组分析，已在关键淋巴细胞发育和信号转导途径中鉴定出新型基因改变，为深入了解与治疗失败相关的高危ALL发病机制提供了线索。在阐明与细胞因子受体样因子2基因（CRLF2）过表达相关的ALL遗传学方面取得了特别进展，CRLF2过表达常伴有编码Ikaros（IKZF1）、Janus激酶1（JAK1）和Janus激酶2（JAK2）以及/或者白细胞介素7受体α链（IL7RA）的基因同时发生激活突变。患有高危CRLF2过表达ALL的儿童和成人复发率高，总生存率不佳。因此，多个研究团队试图通过临床前模型来表征这些基因损伤的生化后果，以期确定新疗法的靶点。这些研究提供了早期数据，表明JAK/STAT和PI3K途径的信号转导抑制剂（STIs）对CRLF2过表达ALL具有应用前景。更多的研究工作仍在继续阐明这些异常信号网络，为将STIs应用于这些高危患者的临床治疗提供理论依据。本综述重点介绍了目前关于CRLF2过表达ALL的发病率、预后意义和生物学特性的知识，以及靶向治疗发展的未来方向。
