Ldb1 is required for Lmo2 oncogene-induced thymocyte self-renewal and T-cell Acute Lymphoblastic Leukemia

Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell Acute Lymphoblastic Leukemia (T-ALL), designated Early T-progenitor ALL (ETP-ALL), that is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. Recent data suggest that Lmo2 may exert these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in a Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in the induction of thymocyte self-renewal, thymocyte radio-resistance and transition to T-ALL in Lmo2 transgenic mice. Ldb1 was also required for acquisition of the pre-leukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Together, these results support a model where Lmo2-induced T-ALL results from failure to down-regulate Ldb/Lmo2 nucleated transcription complexes that normally function to enforce self-renewal in bone marrow hematopoietic progenitors 2 cell types (DN2/3 and DN4), 3 genotypes: C57BL/6 (wild type) – 4 replicates, Lmo2tg – 5 replicates, Lmo2tg; Ldb1-KO – 4 replicates. Total = 28 samples.

原癌基因Lmo2的持续或增强型表达，与一类重症T细胞急性淋巴细胞白血病（T-cell Acute Lymphoblastic Leukemia, T-ALL）密切相关，该亚型被命名为早T前体ALL（Early T-progenitor ALL, ETP-ALL），其特征为未成熟胸腺细胞发生异常自我更新，并随后出现致瘤性转化。近期研究表明，Lmo2可通过作为多亚基转录复合物的组分发挥上述效应，该复合物包含泛适配因子Ldb1，以及碱性螺旋-环-螺旋转录因子（b-HLH）和/或GATA家族转录因子。本研究依托Lmo2转基因T-ALL小鼠模型，通过在胸腺细胞中条件性敲除Ldb1，探究了Ldb1在Lmo2诱导的T-ALL发生过程中的重要性。研究结果证实，在Lmo2转基因小鼠中，Ldb1是胸腺细胞自我更新、胸腺细胞辐射抗性以及向T-ALL转化过程的关键必需因子。未成熟Lmo2转基因胸腺细胞获取白血病前期ETP基因表达特征的过程，同样依赖Ldb1的存在。综上，本研究结果支持如下模型：Lmo2诱导的T-ALL源于无法下调由Ldb/Lmo2成核的转录复合物，这类复合物在正常生理状态下可维持骨髓造血祖细胞两种细胞类型（DN2/3与DN4）的自我更新。本研究设置3种基因型样本：C57BL/6（野生型）——4个生物学重复，Lmo2tg——5个生物学重复，Lmo2tg; Ldb1-KO——4个生物学重复，总样本量共计28例。