MLL is essential for NUP98-HOXA9-induced leukemia

Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation. To identify the regulated genes by the NUP98 moiety of NUP98-HOXA9, we performed gene expression profiling in full-length NUP98-HOXA9- and NUP98-HOXA9 deletion mutant-expressing cells.

涉及NUP98基因（NUP98 gene）的染色体重排，当其与多个伴侣基因形成融合基因时，可见于急性髓系白血病与骨髓增生异常综合征。本研究证实，NUP98-HOXA9融合蛋白的NUP98结构组分中，第二个FG重复结构域（FG repeat domain）对其介导的细胞永生化及白血病发生活性具有关键作用。我们进一步证明，NUP98-HOXA9可通过该FG重复结构域与混合谱系白血病基因（MLL）发生相互作用；且在MLL缺失的背景下，NUP98-HOXA9诱导的细胞永生化与白血病发生过程会受到显著抑制。分子生物学分析显示，MLL对于NUP98-HOXA9靶向募集至HOXA基因座（HOXA locus），以及NUP98-HOXA9介导的HOXA基因表达均不可或缺。本研究数据表明，MLL在NUP98-HOXA9诱发的白血病起始过程中发挥核心作用。为鉴定NUP98-HOXA9的NUP98组分所调控的靶基因，我们分别在表达全长NUP98-HOXA9与表达NUP98-HOXA9缺失突变体的细胞中开展了基因表达谱（gene expression profiling）分析。