Overexpression of Hmga2 activates Igf2bp2 and remodels transcriptional program of Tet2-deficient stem cells in myeloid transformation
Overexpression of Hmga2 activates Igf2bp2 and remodels transcriptional program of Tet2-deficient stem cells in myeloid transformation
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DOI：
10.1038/s41388-020-01629-w
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发表时间：
2021-01-15
期刊：
影响因子：
8
通讯作者：
Sashida, Goro
中科院分区：
文献类型：
--
作者：
Bai, Jie;Yokomizo-Nakano, Takako;Sashida, Goro
高迁移率族AT-钩2（HMGA 2）是一种染色质修饰剂，其过表达已在骨髓增生异常综合征（MDS）和急性髓性白血病（AML）患者中发现。Hmga 2表达水平通过Lin 28 b-Let-7轴和Polycomb抑制复合物2微调，其中Ezh 2的缺失导致造血干细胞中Hmga 2表达的激活。为了阐明HMGA 2的过表达有助于转化携带TET 2驱动突变的干细胞的机制，我们产生了一种表达HMGA 2的Tet 2缺陷小鼠模型，该模型显示MDS和AML的进行性表型。Hmga 2的过度表达重塑了Tet 2缺陷的干细胞和祖细胞的转录程序，导致骨髓细胞分化受损。此外，Hmga 2结合到Igf 2bp 2癌基因的近端区域，并激活其转录，导致Tet 2缺陷型干细胞的自我更新增强，而Tet 2缺陷型干细胞的自我更新被Hmga 2的DNA结合抑制所抑制。这些对转录程序和细胞功能的组合效应对于Tet 2缺陷细胞中的那些并不是多余的。本研究结果阐明了Hmga 2在转化过程中靶向关键的致癌途径，并突出了Hmga 2-Igf 2bp 2轴作为治疗干预的潜在靶点。
High Mobility Group AT-hook 2 (HMGA2) is a chromatin modifier and its overexpression has been found in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Level of Hmga2 expression is fine-tuned by Lin28b-Let-7 axis and Polycomb Repressive Complex 2, in which deletion of Ezh2 leads to activation of Hmga2 expression in hematopoietic stem cells. To elucidate the mechanisms by which the overexpression of HMGA2 helps transformation of stem cells harboring a driver mutation of TET2, we generated an Hmga2-expressing Tet2-deficient mouse model showing the progressive phenotypes of MDS and AML. The overexpression of Hmga2 remodeled the transcriptional program of Tet2-deficient stem and progenitor cells, leading to the impaired differentiation of myeloid cells. Furthermore, Hmga2 was bound to a proximal region of Igf2bp2 oncogene, and activated its transcription, leading to enhancing self-renewal of Tet2-deficient stem cells that was suppressed by inhibition of the DNA binding of Hmga2. These combinatory effects on the transcriptional program and cellular function were not redundant to those in Tet2-deficient cells. The present results elucidate that Hmga2 targets key oncogenic pathways during the transformation and highlight the Hmga2-Igf2bp2 axis as a potential target for therapeutic intervention.