The molecular genetic makeup of acute lymphoblastic leukemia
The molecular genetic makeup of acute lymphoblastic leukemia
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DOI：
10.1182/asheducation-2012.1.389
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发表时间：
2012-12-01
影响因子：
3
通讯作者：
Mullighan, Charles G.
中科院分区：
文献类型：
--
作者：
Mullighan, Charles G.
基因组图谱改变了我们对急性淋巴细胞白血病(ALL)遗传基础的理解。近年来，从微阵列分析和候选基因测序转向了下一代测序。总之，这些方法表明，许多所有亚型的特点是结构重排、亚显微DNA拷贝数改变和序列突变，其中一些对风险分层和靶向治疗干预具有明显的意义。调节淋巴发育的基因突变是ALL的标志，淋巴转录因子基因IKZF1(IKAROS)的变化与B-ALL治疗失败的高风险有关。大约20%的B-ALL病例存在激活激酶信号的基因改变，该改变可能适用于酪氨酸激酶抑制剂的治疗，包括细胞因子受体基因CRLF2的重排；ABL1、JAK2和PDGFRb的重排；以及JAK1和JAK2的突变。全基因组测序也发现了侵袭性T系ALL的新突变靶点，包括造血调节因子(ETV6和RUNX1)、酪氨酸激酶和表观遗传调节因子。未来的挑战是全面识别和实验验证所有导致儿童和成人ALL白血病发生和治疗失败的基因改变，并将基因组图谱应用于临床环境，以指导风险分层和靶向治疗。
Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.