Kettyle Laura M, Lebert-Ghali Charles-Étienne, Grishagin Ivan V, Dickson Glenda J, O'Reilly Paul G, Simpson David A, Bijl Janet J, Mills Ken I, Sauvageau Guy, Thompson Alexander
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK.
Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada.
Cancers (Basel). 2019 Dec 17;11(12):2036. doi: 10.3390/cancers11122036.
High expression of the cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (). Whilst decreased expression acts as a readout for candidate experimental therapies, the necessity of the cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from responsive transgenic mice for conditional deletion of the locus. deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the cluster, indicating dependency. Comparative transcriptome analysis of wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high expressing cancers including MLLr leukemias. Together these findings support dependency for an leukemia on expression and identified candidate drugs for further therapeutic evaluation.
该基因簇的高表达与急性髓系白血病的不良临床预后相关，尤其是那些携带混合谱系白血病基因重排的患者。虽然该基因簇表达降低可作为候选实验性治疗的指标，但尚未充分探索该基因簇对白血病维持的必要性。利用条件性敲除该基因座的反应性转基因小鼠的造血干/祖细胞产生原发性白血病。基因敲除导致增殖和集落形成减少，其中存活的白血病细胞保留了该基因簇的至少一个拷贝，表明存在依赖性。对野生型和基因敲除的白血病细胞进行比较转录组分析，确定了一个独特的基因特征，该特征与关键通路相关，包括癌症中的转录失调、范可尼贫血通路和细胞周期进程。对该基因特征的进一步生物信息学分析确定了一些FDA批准的候选药物，可用于高表达癌症（包括MLLr白血病）的潜在重新利用。这些发现共同支持了白血病对该基因簇表达的依赖性，并确定了候选药物用于进一步的治疗评估。
