Genetic characterization and therapeutic targeting of MYC rearranged T-cell acute lymphoblastic leukemia. Genetic characterization and therapeutic targeting of MYC rearranged T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological tumor that arises from T-cell precursor cells, is often characterized by T cell receptor (TCR) translocations that drive aberrant activation of specific proto-oncogenes. Here, we performed a detailed molecular genetic characterization of a rare but aggressive genetic subtype of human T-ALL, ie. patients that present with a t(8;14)(q24;q11) translocation, in which high MYC levels are driven by enhancer elements of the TCR a/d locus (TCRAD-MYC). Notably, analysis of an extensive series of primary leukemia samples confirmed that TCRAD-MYC translocation positive T-ALLs represent a NOTCH1 independent subtype of T-cell leukemia characterized by aberrant activation of the TAL1 and/or LMO2 transcription factor oncogenes and frequent activation of the PI3K/AKT signaling pathway. From a therapeutic perspective, in vivo drug treatment experiments using primary patient derived xenografts revealed that TCRAD-MYC positive T-ALLs are sensitive to BET bromodomain inhibition, providing a rationale to develop BRD4 inhibitors as an adjuvant therapy for this rare, but genetically well-defined, high-risk subtype of human leukemia. Overall design: We performed H3K27ac chromatin immunoprecipitation (ChIP) sequencing analysis on the t(8;14)(q24;q11) positive MOLT16 cells to study the enhancer landscape in proximity of the TCRAD locus, which is involved in TCRAD-MYC translocation in a rare T-ALL subgroup.

T细胞急性淋巴细胞白血病（T-cell acute lymphoblastic leukemia, T-ALL）是一种起源于T细胞前体细胞的侵袭性血液肿瘤，常以驱动特定原癌基因异常激活的T细胞受体（T cell receptor, TCR）易位为特征。本研究针对一类罕见但侵袭性极强的人类T-ALL遗传亚型——即携带t(8;14)(q24;q11)易位的患者——开展了详细的分子遗传学表征：该易位中MYC基因的高表达由TCR α/δ位点（TCR α/d locus, TCRAD）的增强子元件所驱动，即TCRAD-MYC易位。值得注意的是，对大规模原发性白血病样本队列的分析证实，携带TCRAD-MYC易位的T-ALL属于NOTCH1非依赖型T细胞白血病亚型，其特征为TAL1和/或LMO2转录因子癌基因的异常激活，以及PI3K/AKT信号通路的频繁活化。从治疗视角来看，利用原发性患者来源异种移植瘤模型开展的体内药物实验显示，携带TCRAD-MYC易位的T-ALL对BET溴结构域抑制剂敏感，这为将BRD4抑制剂开发为该罕见但遗传特征明确的高危人类白血病亚型的辅助治疗手段提供了理论依据。总体实验设计：本研究对携带t(8;14)(q24;q11)易位的MOLT16细胞进行了H3K27乙酰化组蛋白染色质免疫共沉淀（chromatin immunoprecipitation, ChIP）测序分析，以研究TCRAD位点附近的增强子调控图谱——该位点参与了罕见T-ALL亚组中的TCRAD-MYC易位事件。