Table_1_The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia.XLSX

ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.

ETV6-RUNX1基因几乎仅与儿童B细胞急性淋巴细胞白血病（B-ALL）相关联，然而，ETV6-RUNX1表达对B细胞白血病发生过程中细胞谱系决策的影响尚完全未知。临床上，ETV6-RUNX1前白血病克隆在新生儿脐带血中频繁发现，但仅有少数携带者因继发性基因变异而发展为B-ALL。对导致首次转化步骤的机制的理解，将极大推动非毒性预防干预措施的发展。通过遗传谱系追踪，我们考察了ETV6-RUNX1通过细胞特异性Cre介导的从内源性Etv6基因座激活ETV6-RUNX1的能力，以指导造血谱系中的恶性表型。本研究表明，虽然ETV6-RUNX1具有引发T和B淋巴系恶性肿瘤的倾向，但决定肿瘤细胞身份的是第二次打击。为了引发白血病，两次致癌打击必须发生在造血/祖细胞发育的早期阶段，而不是在已经分化的B细胞中。根据第二次打击的性质，由此产生的B-ALL呈现出不同的实体，这些实体可以根据其基因表达谱明确区分。我们的发现为ETV6-RUNX1+ B-ALL早期发展的机制提供了新的见解，并可能对潜在的开发ETV6-RUNX1+ B-ALL预防策略具有重大意义。