Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia.
Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia.
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DOI：
10.3389/fonc.2014.00054
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发表时间：
2014
影响因子：
4.7
通讯作者：
Hunger SP
中科院分区：
文献类型：
--
作者：
Bernt KM;Hunger SP
t(9;22)（q34;q11）或费城染色体产生BCR-ABL1融合基因，编码嵌合BCR-ABL1蛋白。3-4%的儿童急性淋巴细胞白血病（Ph+ ALL）和25%的成人急性淋巴细胞白血病病例中存在这种细胞。在酪氨酸激酶抑制剂（TKI）出现之前，尽管在首次缓解时使用强化化疗和频繁的造血干细胞移植（HSCT），但Ph+ ALL仍与非常差的预后相关。TKIs的发展彻底改变了Ph+ ALL的治疗。在强化化疗中加入第一代ABL1类TKI伊马替尼显着提高了Ph+ ALL儿童的生存率，并确定许多患者无需HSCT即可治愈。与此同时，通过仔细绘制BCR-ABL1下游通路，发现b细胞发育的主要调节因子（如IKZF1 （Ikaros）、PAX5和早期b细胞因子（EBF））的突变，识别Ph+ ALL的复杂克隆结构，以及描述导致复发和耐药性的基因组、表观遗传和信号异常，对Ph+ ALL的机制理解呈指数级扩展。然而，许多重要的基础和临床问题仍未得到解答。目前的临床试验是在新诊断的Ph+ ALL患者中测试第二代TKIs。目前还没有确定最佳的治疗时间和最佳的化疗骨干。HSCT在首次缓解和移植后TKI治疗中的作用也需要进一步研究。此外，在机制水平上继续深入了解Ph+ ALL，并将发现转化为互补的靶向方法，这将是至关重要的。扩大靶向治疗有望降低这种高风险疾病的毒性和提高生存率，这为如何将靶向治疗纳入其他高风险白血病的治疗提供了一个范例。
The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR–ABL1 fusion gene encoding for a chimeric BCR–ABL1 protein. It is present in 3–4% of pediatric acute lymphoblastic leukemia (Ph+ ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph+ ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph+ ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph+ ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph+ ALL expanded exponentially through careful mapping of pathways downstream of BCR–ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph+ ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph+ ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph+ ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias.