Ishihara Daishi, Hasegawa Atsushi, Hirano Ikuo, Engel James Douglas, Yamamoto Masayuki, Shimizu Ritsuko
Department of Molecular Hematology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8575, Japan.
Exp Hematol Oncol. 2024 Feb 26;13(1):24. doi: 10.1186/s40164-024-00492-9.
Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.
转录因子GATA1控制着红细胞系和巨核细胞系中增殖、分化和凋亡之间的微妙平衡。除全长GATA1外，还有一种GATA1异构体GATA1s，它缺乏氨基末端反式激活结构域。导致仅产生GATA1s的体细胞GATA1突变似乎是唐氏综合征新生儿中一种称为短暂性骨髓增殖性疾病（TMD）的白血病前期病症发展所必需且充分的条件。潜伏性TMD原始细胞随后的克隆进化会导致急性巨核细胞白血病（AMKL）的发生。我们最初建立了只表达GATA1s的转基因小鼠，这些小鼠表现出未成熟巨核细胞的过度增殖，从而模拟人类TMD；然而，这些小鼠从未发展为AMKL。在此，我们报告表达中等水平GATA1s（即与内源性GATA1大致相当的水平）的转基因小鼠在年轻成年期易患AMKL。然而，当GATA1s的表达水平显著超过内源性GATA1时，白血病的发展以剂量依赖的方式受到抑制。如果祖细胞中GATA1s的转基因增加量仍然很小，GATA1s就不足以支持巨核细胞祖细胞的终末成熟，因此祖细胞持续存在，导致获得额外基因修饰的概率增加。相反，更丰富的GATA1s表达弥补了这种成熟障碍，使巨核细胞祖细胞能够完全分化。这项研究为临床观察提供了证据，即GATA1s的丰度与唐氏综合征中向AMKL的进展密切相关。
