Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.
Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, Basel, Switzerland.
Blood. 2018 Jan 4;131(1):95-107. doi: 10.1182/blood-2017-05-786962. Epub 2017 Oct 30.
Mixed lineage leukemia (MLL) represents a genetically distinct and aggressive subset of human acute leukemia carrying chromosomal translocations of the gene. These translocations result in oncogenic fusions that mediate aberrant recruitment of the transcription machinery to MLL target genes. The N-terminus of MLL and MLL-fusions form a complex with lens epithelium-derived growth factor (LEDGF/p75; encoded by the gene) and MENIN. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with the chromatin. Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL-fusion-mediated transformation and for the expression of downstream MLL-regulated genes such as and In light of developing a therapeutic strategy targeting this complex, understanding the function of LEDGF/p75 in normal hematopoiesis is crucial. We generated a conditional knockout mouse model in the hematopoietic compartment and examined the effects of LEDGF/p75 depletion in postnatal hematopoiesis and the initiation of MLL leukemogenesis. knockout mice were viable but showed several defects in hematopoiesis, reduced colony-forming activity in vitro, decreased expression of genes in the hematopoietic stem cells, and decreased MLL occupancy at MLL target genes. Finally, in vitro and in vivo experiments showed that LEDGF/p75 is dispensable for steady-state hematopoiesis but essential for the initiation of MLL-mediated leukemia. These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatment of -rearranged leukemia.
混合谱系白血病（MLL）代表了一类具有独特遗传学特征和侵袭性的人类急性白血病亚群，其携带基因的染色体易位。这些易位导致致癌融合，从而介导转录机制异常募集到 MLL 靶基因。MLL 和 MLL 融合的 N 端与晶状体上皮衍生生长因子（LEDGF/p75；由基因编码）和 MENIN 形成复合物。该复合物有助于 MLL 和 MLL 融合多蛋白复合物与染色质的关联。几项研究表明，MENIN 和 LEDGF/p75 对于有效的 MLL 融合介导的转化以及下游 MLL 调节基因（如和）的表达都是必需的。鉴于开发靶向该复合物的治疗策略，了解 LEDGF/p75 在正常造血中的功能至关重要。我们在造血细胞中生成了一个条件性基因敲除小鼠模型，并研究了 LEDGF/p75 耗竭对出生后造血和 MLL 白血病发生的影响。基因敲除小鼠是存活的，但在造血中表现出多种缺陷，体外集落形成活性降低，造血干细胞中基因表达减少，以及 MLL 靶基因上的 MLL 占有率降低。最后，体外和体内实验表明，LEDGF/p75 对于稳态造血不是必需的，但对于 MLL 介导的白血病的起始是必需的。这些数据证实了 MLL-LEDGF/p75 相互作用是治疗基因重排白血病的一个新靶点。
