Redefining the biological basis of lineage-ambiguous leukemia through genomics: BCL11B deregulation in acute leukemias of ambiguous lineage.
Redefining the biological basis of lineage-ambiguous leukemia through genomics: BCL11B deregulation in acute leukemias of ambiguous lineage.
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DOI：
10.1016/j.beha.2021.101329
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Mullighan CG
中科院分区：
文献类型：
--
作者：
Montefiori LE;Mullighan CG
由于对发病机制的了解有限、依赖免疫表型对疾病进行分类以及缺乏合理的方法来指导选择适当的治疗方法，不明谱系急性白血病 (ALAL)，包括混合表型急性白血病 (MPAL) 和相关实体，如早期 T 细胞前体急性白血病 (ETP-ALL)，仍然面临诊断和临床挑战。最近利用基因组测序和补充方法的研究提供了重要的见解，这些见解正在改变此类白血病的分类和潜在的治疗方式。几种复发性基因组改变定义了跨免疫表型实体的白血病，例如 ZNF384 重排的儿童 B-ALL 和 B/髓样 MPAL，以及 BCL11B 重排的 T/髓样 MPAL、ETP-ALL 和 AML。相比之下，一些 MPAL 病例代表典型的 ALL/AML 实体，表现出谱系异常。对于许多 ALAL 病例，实验方法表明谱系异常是由造血干细胞和祖细胞获得基础基因改变引起的。确定最佳治疗方法需要在前瞻性研究中对统一治疗的 ALAL 患者进行基因组表征，但包括激酶抑制剂和 BH3 模拟物在内的几种方法可能对 ALAL 亚型有效。
Acute leukemias of ambiguous lineage (ALAL), including mixed phenotype acute leukemia (MPAL) and related entities such as early T-cell precursor acute leukemia (ETP-ALL), remain diagnostic and clinical challenges dues to limited understanding of pathogenesis, reliance of immunophenotyping to classify disease, and the lack of a rational approach to guide selection of appropriate therapy. Recent studies utilizing genomic sequencing and complementary approaches have provided key insights that are changing the way in which such leukemias are classified, and potentially, treated. Several recurrent genomic alterations define leukemias that straddle immunophenotypic entities, such as ZNF384-rearranged childhood B-ALL and B/myeloid MPAL, and BCL11B-rearranged T/myeloid MPAL, ETP-ALL and AML. In contrast, some cases of MPAL represent canonical ALL/AML entities exhibiting lineage aberrancy. For many cases of ALAL, experimental approaches indicate lineage aberrancy arises from acquisition of a founding genetic alterations into a hematopoietic stem and progenitor cell. Determination of optimal therapeutic approach requires genomic characterization of uniformly treated ALAL patients in prospective studies, but several approaches, including kinase inhibitors and BH3 mimetics may be efficacious in subsets of ALAL.
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