A mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia [HTS]

The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL. Genome-wide profiling of mRNA levels in p210 transduced murine Xbp1 fl/+ pre-B cells with ERT2 (XE.1,2,3) and Cre- ERT2  (XC.1,2,3).

浆细胞转录因子XBP1（X盒结合蛋白1，X-box binding protein 1）对B细胞终末分化为浆细胞至关重要，但此前尚未明确其在B细胞发育早期阶段的功能。本研究证实，XBP1不仅在B细胞早期发育及前B细胞存活过程中发挥关键作用，还可保护前B细胞急性淋巴细胞白血病（pre-B acute lymphoblastic leukemia, pre-B ALL）细胞。在pre-B ALL亚型中，XBP1在费城染色体阳性急性淋巴细胞白血病（Philadelphia chromosome-positive acute lymphoblastic leukemia, Ph+ ALL）亚型中呈现低甲基化状态且表达水平最高。在Ph+ ALL小鼠模型中，经Cre介导的XBP1基因敲除会削弱细胞增殖与存活能力，并延长白血病荷瘤小鼠的生存期。值得注意的是，XBP1的表达水平受STAT5（信号转导与转录激活因子5，signal transducer and activator of transcription 5）的正向转录调控，同时受BACH2（BTB域和CNC同源物2，BTB domain and CNC homolog 2）与BCL6（B细胞淋巴瘤6，B-cell lymphoma 6）的负向转录调控。两项临床试验数据显示，高危急性淋巴细胞白血病患者在确诊时的高XBP1表达水平可作为不良预后的预测指标。临床前研究表明，靶向IRE1（肌醇依赖酶1，inositol-requiring enzyme 1）依赖性XBP1激活的小分子抑制剂可诱导患者来源的pre-B ALL细胞死亡，并影响移植受体小鼠的白血病起始能力。综上，本系列研究证实XBP1是关键的细胞存活因子，同时可作为克服pre-B ALL耐药性的潜在治疗靶点。本数据集包含经p210酪氨酸激酶转导的小鼠Xbp1条件性敲除杂合子前B细胞（Xbp1 fl/+ pre-B cells），分别转染突变型雌激素受体ERT2（样本编号XE.1、XE.2、XE.3）与Cre重组酶融合ERT2（Cre-ERT2，样本编号XC.1、XC.2、XC.3）的全基因组mRNA表达谱分析数据。