Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Oncogene. 2021 Feb;40(8):1531-1541. doi: 10.1038/s41388-020-01629-w. Epub 2021 Jan 15.
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.
高迁移率族 AT 钩 2（HMGA2）是一种染色质修饰物，其过表达已在骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者中发现。Hmga2 的表达水平受到 Lin28b-Let-7 轴和多梳抑制复合物 2 的精细调节，其中 Ezh2 的缺失导致造血干细胞中 Hmga2 表达的激活。为了阐明 HMGA2 的过表达如何帮助携带 TET2 驱动突变的干细胞转化的机制，我们生成了一个表达 Hmga2 的 Tet2 缺陷型小鼠模型，该模型表现出 MDS 和 AML 的进行性表型。Hmga2 的过表达重塑了 Tet2 缺陷型干细胞和祖细胞的转录程序，导致髓系细胞分化受损。此外，Hmga2 与 Igf2bp2 癌基因的近端区域结合，并激活其转录，导致 Tet2 缺陷型干细胞的自我更新增强，而 Hmga2 的 DNA 结合抑制则抑制了这种自我更新。这些对转录程序和细胞功能的组合效应与 Tet2 缺陷型细胞中的那些并不冗余。本研究结果阐明了 Hmga2 在转化过程中靶向关键致癌途径，并强调了 Hmga2-Igf2bp2 轴作为治疗干预的潜在靶点。
