Ueda Koki, Ikeda Kazuhiko, Ikezoe Takayuki, Harada-Shirado Kayo, Ogawa Kazuei, Hashimoto Yuko, Sano Takahiro, Ohkawara Hiroshi, Kimura Satoshi, Shichishima-Nakamura Akiko, Nakamura Yuichi, Shikama Yayoi, Mori Tsutomu, Mason Philip J, Bessler Monica, Morishita Soji, Komatsu Norio, Shide Kotaro, Shimoda Kazuya, Koide Shuhei, Aoyama Kazumasa, Oshima Motohiko, Iwama Atsushi, Takeishi Yasuchika
Department of Hematology.
Department of Blood Transfusion and Transplantation Immunology.
Blood Adv. 2017 Jun 14;1(15):1001-1015. doi: 10.1182/bloodadvances.2017004457. eCollection 2017 Jun 27.
High-mobility group AT-hook 2 () is crucial for the self-renewal of fetal hematopoietic stem cells (HSCs) but is downregulated in adult HSCs via repression by and the polycomb-recessive complex 2 (PRC2) including EZH2. The messenger RNA (mRNA) level is often elevated in patients with myelofibrosis that exhibits an advanced myeloproliferative neoplasm (MPN) subtype, and deletion of promotes the progression of severe myelofibrosis in mice with upregulation of several oncogenes such as . However, the direct role of in the pathogenesis of MPNs remains unknown. To clarify the impact of on MPNs carrying the driver mutation, we generated Δ/ mice overexpressing Hmga2 due to deletion of the 3' untranslated region. Compared with mice, Δ/ mice exhibited more severe leukocytosis, anemia and splenomegaly, and shortened survival, whereas severity of myelofibrosis was comparable. Δ/ cells showed a greater repopulating ability that reproduced the severe MPN compared with cells in serial bone marrow transplants, indicating that Hmga2 promotes MPN progression at the HSC level. Hmga2 also enhanced apoptosis of erythroblasts that may worsen anemia. Relative to hematopoietic stem and progenitor cells (HSPCs), over 30% of genes upregulated in Δ/ HSPCs overlapped with those derepressed by loss in / HSPCs, suggesting that Hmga2 may facilitate upregulation of Ezh2 targets. Correspondingly, deletion of ameliorated anemia and splenomegaly in / mice, and suppression and PRC2 mutations correlated with the elevated mRNA levels in patients with MPNs, especially myelofibrosis. These findings suggest the crucial role of HMGA2 in MPN progression.
高迁移率族AT钩蛋白2（HMGA2）对胎儿造血干细胞（HSC）的自我更新至关重要，但在成年HSC中通过被包括EZH2在内的SUZ12和多梳抑制复合物2（PRC2）抑制而表达下调。在表现为晚期骨髓增殖性肿瘤（MPN）亚型的骨髓纤维化患者中，HMGA2信使核糖核酸（mRNA）水平通常升高，并且HMGA2的缺失会促进携带如JAK2等几种致癌基因上调的Vav-Cre;Hmga2fl/fl小鼠发生严重骨髓纤维化。然而，HMGA2在MPN发病机制中的直接作用仍不清楚。为了阐明HMGA2对携带驱动突变的MPN的影响，我们通过缺失3'非翻译区生成了过表达Hmga2的Δ/小鼠。与野生型小鼠相比，Δ/小鼠表现出更严重的白细胞增多、贫血和脾肿大，并且生存期缩短，而骨髓纤维化的严重程度相当。在连续骨髓移植中，与野生型细胞相比，Δ/细胞显示出更强的再增殖能力，重现了严重的MPN，表明Hmga2在HSC水平促进MPN进展。Hmga2还增强了红系祖细胞的凋亡，这可能会使贫血恶化。相对于野生型造血干祖细胞（HSPC），Δ/HSPC中上调的基因超过30%与在SUZ12缺失的/HSPC中去抑制的基因重叠，这表明Hmga2可能促进Ezh2靶标的上调。相应地，SUZ12的缺失改善了Vav-Cre;Hmga2fl/fl小鼠的贫血和脾肿大，并且SUZ12抑制和PRC2突变与MPN患者，尤其是骨髓纤维化患者中升高的HMGA2 mRNA水平相关。这些发现表明HMGA2在MPN进展中起关键作用。
