Smith K S, Rhee J W, Naumovski L, Cleary M L
Department of Pathology, Stanford University Medical Center, Stanford, California 94305, USA.
Mol Cell Biol. 1999 Jun;19(6):4443-51. doi: 10.1128/MCB.19.6.4443.
The hepatic leukemia factor (HLF) gene codes for a basic region-leucine zipper (bZIP) protein that is disrupted by chromosomal translocations in a subset of pediatric acute lymphoblastic leukemias. HLF undergoes fusions with the E2A gene, resulting in chimeric E2a-Hlf proteins containing the E2a transactivation domains and the Hlf bZIP DNA binding and dimerization motifs. To investigate the in vivo role of this chimeric bZIP protein in oncogenic transformation, its expression was directed to the lymphoid compartments of transgenic mice. Within the thymus, E2a-Hlf induced profound hypoplasia, premature involution, and progressive accumulation of a T-lineage precursor population arrested at an early stage of maturation. In the spleen, mature T cells were present but in reduced numbers, and they lacked expression of the transgene, suggesting further that E2a-Hlf expression was incompatible with T-cell differentiation. In contrast, mature splenic B cells expressed E2a-Hlf but at lower levels and without apparent adverse or beneficial effects on their survival. Approximately 60% of E2A-HLF mice developed lymphoid malignancies with a mean latency of 10 months. Tumors were monoclonal, consistent with a requirement for secondary genetic events, and displayed phenotypes of either mid-thymocytes or, rarely, B-cell progenitors. We conclude that E2a-Hlf disrupts the differentiation of T-lymphoid progenitors in vivo, leading to profound postnatal thymic depletion and rendering B- and T-cell progenitors susceptible to malignant transformation.
肝白血病因子（HLF）基因编码一种碱性区域-亮氨酸拉链（bZIP）蛋白，在一部分儿童急性淋巴细胞白血病中，该基因会因染色体易位而被破坏。HLF与E2A基因发生融合，产生嵌合的E2a-Hlf蛋白，其包含E2a反式激活结构域以及Hlf bZIP DNA结合和二聚化基序。为了研究这种嵌合bZIP蛋白在致癌转化中的体内作用，将其表达定向到转基因小鼠的淋巴细胞淋巴隔室。在胸腺内，E2a-Hlf诱导严重发育不全、过早退化以及在成熟早期停滞的T细胞系前体细胞群体的逐渐积累。在脾脏中，存在成熟T细胞，但数量减少，并且它们缺乏转基因表达，这进一步表明E2a-Hlf表达与T细胞分化不相容。相比之下，成熟的脾脏B细胞表达E2a-Hlf，但水平较低，并且对其存活没有明显的不利或有益影响。大约60%的E2A-HLF小鼠发生淋巴恶性肿瘤，平均潜伏期为10个月。肿瘤是单克隆的，符合对继发性遗传事件的需求，并表现出中胸腺细胞或很少见的B细胞祖细胞的表型。我们得出结论，E2a-Hlf在体内破坏T淋巴细胞祖细胞的分化，导致出生后胸腺严重耗竭，并使B细胞和T细胞祖细胞易发生恶性转化。
