Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Int J Hematol. 2023 Aug;118(2):277-287. doi: 10.1007/s12185-023-03612-z. Epub 2023 May 13.
The NUP98::NSD1 fusion gene is associated with extremely poor prognosis in patients with acute myeloid leukemia (AML). NUP98::NSD1 induces self-renewal and blocks differentiation of hematopoietic stem cells, leading to development of leukemia. Despite its association with poor prognosis, targeted therapy for NUP98::NSD1-positive AML is lacking, as the details of NUP98::NSD1 function are unknown. Here, we generated 32D cells (a murine interleukin-3 (IL-3)-dependent myeloid progenitor cell line) expressing mouse Nup98::Nsd1 to explore the function of NUP98::NSD1 in AML, including comprehensive gene expression analysis. We identified two properties of Nup98::Nsd1 + 32D cells in vitro. First, Nup98::Nsd1 promoted blocking of AML cell differentiation, consistent with a previous report. Second, Nup98::Nsd1 increased dependence on IL-3 for cell proliferation, due to overexpression of the alpha subunit of the IL-3 receptor (IL3-RA, also known as CD123). Consistent with our in vitro data, IL3-RA was also upregulated in samples from patients with NUP98::NSD1-positive AML. These results highlight CD123 as a potential new therapeutic target in NUP98::NSD1-positive AML.
NUP98::NSD1 融合基因与急性髓系白血病（AML）患者的极差预后相关。NUP98::NSD1 诱导造血干细胞自我更新并阻断其分化，导致白血病的发生。尽管 NUP98::NSD1 与预后不良相关，但缺乏针对 NUP98::NSD1 阳性 AML 的靶向治疗，因为 NUP98::NSD1 的功能细节尚不清楚。在这里，我们生成了表达小鼠 Nup98::Nsd1 的 32D 细胞（一种小鼠白细胞介素 3（IL-3）依赖性髓系祖细胞系），以探索 NUP98::NSD1 在 AML 中的功能，包括全面的基因表达分析。我们在体外鉴定了 Nup98::Nsd1+32D 细胞的两个特性。首先，Nup98::Nsd1 促进 AML 细胞分化阻断，与之前的报道一致。其次，Nup98::Nsd1 通过过度表达白细胞介素 3 受体（IL3-RA，也称为 CD123）的α亚基增加对细胞增殖的依赖。与我们的体外数据一致，NUP98::NSD1 阳性 AML 患者样本中也上调了 IL3-RA。这些结果突出了 CD123 作为 NUP98::NSD1 阳性 AML 中潜在的新治疗靶点。
