Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia.

中文翻译：

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混合表型急性白血病的遗传基础和细胞起源


混合表型急性白血病 (MPAL) 是一种高危白血病亚型，具有髓系和淋巴系特征、有限的遗传特征，并且在适当的治疗方面缺乏共识。在这里，我们表明 MPAL 的两种主要亚型，T/髓样 (T/M) 和 B/髓样 (B/M)，在遗传上是不同的。 ZNF384 重排在 B/M MPAL 中常见，双等位基因 WT1 改变在 T/M MPAL 中常见，其与早期 T 细胞前体急性淋巴细胞白血病具有相同的基因组特征。我们证明 MPAL 的瘤内免疫表型异质性特征与体细胞遗传变异无关，基础病变出现在原始造血祖细胞中，并且个体表型亚群可以在体内重建免疫表型多样性。这些发现表明，肿瘤细胞的谱系混杂是由起源细胞和基础病变细胞引起的，而不是不同基因组改变的积累。此外，这些发现将 MPAL 定位在未成熟白血病谱系中，并为未来 MPAL 潜在治疗方法的临床试验提供了一个遗传信息框架。一项大规模基因组学研究表明，细胞起源和基础突变决定疾病亚型并导致混合表型急性白血病中多种造血谱系定义抗原的表达。