Department of Hematology-Oncology, CIMA Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain.
Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
Nat Commun. 2022 Dec 9;13(1):7619. doi: 10.1038/s41467-022-35192-7.
Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34 cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients.
骨髓增生异常综合征（MDS）是一种造血干细胞（HSC）恶性肿瘤，其特征是无效造血，在老年人中的发病率增加。在这里，我们分析了从年轻和老年健康成年人以及 MDS 患者中纯化的人类 HSC 的转录组，确定了不同表达模式下的转录变化。虽然与年龄相关的病变似乎使 HSC 易于向髓样转化，但疾病特异性改变可能引发 MDS 的发展。在 MDS 特异性病变中，我们检测到转录因子 DNA 损伤诱导转录物 3（DDIT3）的上调。在人类健康 HSC 中过表达 DDIT3 会诱导 MDS 样转录状态，并伴有红细胞生成障碍，这与正常红细胞分化所需的转录程序的激活失败有关。此外，在贫血 MDS 患者的 CD34 细胞中敲低 DDIT3 能够恢复红细胞生成。这些结果确定了 DDIT3 是红细胞生成障碍的驱动因素，也是恢复 MDS 患者特征性的低效红细胞分化的潜在治疗靶点。
