Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Nat Genet. 2023 Jul;55(7):1186-1197. doi: 10.1038/s41588-023-01429-4. Epub 2023 Jun 19.
In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1 preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms.
在 BCR-ABL1 淋巴母细胞白血病中，对酪氨酸激酶抑制剂（TKI）的治疗异质性，特别是在 BCR-ABL1 中缺乏激酶结构域突变的情况下，目前了解甚少。通过深入的分子分析，我们发现了三种 BCR-ABL1 淋巴母细胞白血病的转录组亚型，每种亚型均代表 B 细胞祖细胞分化阶段的成熟阻滞。较早的阻滞与谱系混杂、治疗耐药和患者预后不良有关。较晚的阻滞与谱系保真度、持久的白血病缓解和改善的患者预后有关。每种成熟阻滞都有特定的基因组事件标记，这些事件控制着 B 细胞发育过程中的不同转变点。有趣的是，这些事件在从患者中分离的 BCR-ABL1 白血病前干细胞中不存在，这支持转录组表型是由白血病起始事件下游决定的。总的来说，我们的数据表明，治疗反应和 TKI 疗效是这种白血病转化时分化阶段的意外结果。
