伊罗齐转录因子基因IRX3在20-30%的急性髓系白血病（AML）中高度表达，并对病理诊断的分化阻滞起到作用。IRX3之下约220kB处的第8内含子FTO序列显示组蛋白乙酰化、DNA甲基化以及与IRX3启动子之间的接触，在转录因子IRX3表达中具有相关性。删除这些内含子元素证实其在积极调控IRX3中的作用。RNA测序揭示了源自这个位点的长非编码（lnc）转录本。FTO-lncAML的削弱（KD）诱导AML细胞的分化，降低克隆活性，并减少FTO第8内含子与IRX3启动子的接触。尽管FTO-lncAML KD和IRX3 KD都能诱导细胞分化，但是只有FTO-lncAML KD导致HOXA基因的下调，表明该转录本在转录水平上具有转活性。FTO-lncAML高表达的AML样本表达了更高水平的HOXA基因和较低水平的分化基因。因此，在FTO第8内含子中存在一个由聚集的增强子元素和长非编码RNA组成的调控模块，在人类AML中起到阻碍髓样细胞分化的作用。© 2023 作者们。

Iroquois transcription factor gene IRX3 is highly expressed in 20-30% of acute myeloid leukemia (AML) and contributes to the pathognomonic differentiation block. Intron 8 FTO sequences ∼220kB downstream of IRX3 exhibit histone acetylation, DNA methylation, and contacts with the IRX3 promoter, which correlate with IRX3 expression. Deletion of these intronic elements confirms a role in positively regulating IRX3. RNAseq revealed long non-coding (lnc) transcripts arising from this locus. FTO-lncAML knockdown (KD) induced differentiation of AML cells, loss of clonogenic activity, and reduced FTO intron 8:IRX3 promoter contacts. While both FTO-lncAML KD and IRX3 KD induced differentiation, FTO-lncAML but not IRX3 KD led to HOXA downregulation suggesting transcript activity in trans. FTO-lncAMLhigh AML samples expressed higher levels of HOXA and lower levels of differentiation genes. Thus, a regulatory module in FTO intron 8 consisting of clustered enhancer elements and a long non-coding RNA is active in human AML, impeding myeloid differentiation.© 2023 The Authors.