MicroRNAs (miRNAs) are commonly deregulated in acute myeloid leukemia (AML), affecting critical genes not only through direct targeting, but also through modulation of downstream effectors. Homeobox (Hox) genes balance self-renewal, proliferation, cell death, and differentiation in many tissues and aberrant Hox gene expression can create a predisposition to leukemogenesis in hematopoietic cells. However, possible linkages between the regulatory pathways of Hox genes and miRNAs are not yet fully resolved. We identified miR-708 to be upregulated in Hoxa9/Meis1 AML inducing cell lines as well as in AML patients. We further showed Meis1 directly targeting miR-708 and modulating its expression through epigenetic transcriptional regulation. CRISPR/Cas9 mediated knockout of miR-708 in Hoxa9/Meis1 cells delayed disease onset in vivo, demonstrating for the first time a pro-leukemic contribution of miR-708 in this context. Overexpression of miR-708 however strongly impeded Hoxa9 mediated transformation and homing capacity in vivo through modulation of adhesion factors and induction of myeloid differentiation. Taken together, we reveal miR-708, a putative tumor suppressor miRNA and direct target of Meis1, as a potent antagonist of the Hoxa9 phenotype but an effector of transformation in Hoxa9/Meis1. This unexpected finding highlights the yet unexplored role of miRNAs as indirect regulators of the Hox program during normal and aberrant hematopoiesis.

中文翻译：

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MicroRNA-708是骨髓细胞中Hoxa9程序的新型调节剂。

MicroRNA（miRNA）通常在急性髓细胞性白血病（AML）中被解除调节，不仅通过直接靶向，而且通过调节下游效应子来影响关键基因。同源盒（Hox）基因在许多组织中平衡自我更新，增殖，细胞死亡和分化，而异常的Hox基因表达可以在造血细胞中促成白血病发生。但是，Hox基因和miRNA的调节途径之间的可能联系尚未完全解决。我们发现在Hoxa9 / Meis1 AML诱导细胞系以及AML患者中，miR-708被上调。我们进一步显示Meis1直接靶向miR-708，并通过表观遗传转录调控调节其表达。CRISPR / Cas9介导的Hoxa9 / Meis1细胞中miR-708的敲除延迟了体内疾病的发作，在这种情况下，首次证明了miR-708的促白血病作用。然而，miR-708的过表达通过调节粘附因子和诱导髓样分化而强烈阻碍了Hoxa9介导的体内转化和归巢能力。两者合计，我们揭示了miR-708，一种假定的抑癌基因miRNA和Meis1的直接靶标，它是Hoxa9表型的有效拮抗剂，但在Hoxa9 / Meis1中具有转化作用。这一出乎意料的发现突显了在正常和异常造血过程中，miRNA作为Hox程序的间接调节因子的尚未探索的作用。然而，miR-708的过表达通过调节粘附因子和诱导髓样分化而强烈阻碍了Hoxa9介导的体内转化和归巢能力。两者合计，我们揭示了miR-708，一种假定的抑癌基因miRNA和Meis1的直接靶标，它是Hoxa9表型的有效拮抗剂，但在Hoxa9 / Meis1中具有转化作用。这一出乎意料的发现突显了在正常和异常造血过程中，miRNA作为Hox程序的间接调节因子的尚未探索的作用。然而，miR-708的过表达通过调节粘附因子和诱导髓样分化而强烈阻碍了Hoxa9介导的体内转化和归巢能力。两者合计，我们揭示了miR-708，一种假定的抑癌基因miRNA和Meis1的直接靶标，它是Hoxa9表型的有效拮抗剂，但在Hoxa9 / Meis1中具有转化作用。这一出乎意料的发现突显了在正常和异常造血过程中，miRNA作为Hox程序的间接调节因子的尚未探索的作用。