Fournier Marilaine, Dubuissez Marion, Neault Mathieu, Delisle Jean-Sébastien, Mallette Frédérick A, Melichar Heather J
Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada; Department of Microbiology & Immunology, Goodman Cancer Institute, McGill University, Montréal, Quebec, Canada.
Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Quebec, Canada.
Exp Hematol. 2025 Jul;147:104791. doi: 10.1016/j.exphem.2025.104791. Epub 2025 Apr 20.
NUP98-KDM5A (NK5) is an oncogenic fusion protein implicated in the development of several types of acute myeloid leukemia (AML) in humans, including rare pediatric acute megakaryoblastic leukemia (AMKL). NK5 expression in murine hematopoietic progenitor cells can induce AML in mice. However, the limited number of animals and phenotypic markers used in previous studies preclude the full characterization of the AML subtypes that develop. We used NK5-transduced hematopoietic progenitor cells from murine fetal liver to generate a large cohort of mice. We then assessed the expression of a panel of myeloid markers to characterize the lineage of leukemic blasts using flow cytometry. Finally, we used bioinformatic tools to perform an unbiased analysis of mouse-to-mouse heterogeneity in leukemic cellular phenotypes. We identified phenotypically distinct subgroups among the NK5 leukemias that were predominantly segregated based on the expression of the AMKL-associated marker CD41. Our findings indicate that NK5 expression in fetal liver cells causes different types of leukemia similar in proportion to that observed in pediatric patients. The heterogeneity and mixed phenotypes observed might explain the difficulty in accurately diagnosing leukemia in some patients carrying the NK5 fusion. In addition, this approach may enable the identification of the molecular or cellular basis of the diverse NK5-driven AML types.
NUP98-KDM5A（NK5）是一种致癌融合蛋白，与人类多种类型的急性髓系白血病（AML）的发生有关，包括罕见的儿童急性巨核细胞白血病（AMKL）。NK5在小鼠造血祖细胞中的表达可在小鼠中诱导AML。然而，先前研究中使用的动物数量有限且表型标记物较少，无法全面表征所产生的AML亚型。我们使用来自小鼠胎儿肝脏的经NK5转导的造血祖细胞生成了大量小鼠群体。然后，我们评估了一组髓系标记物的表达，以使用流式细胞术表征白血病母细胞的谱系。最后，我们使用生物信息学工具对白血病细胞表型中的小鼠间异质性进行无偏分析。我们在NK5白血病中鉴定出表型不同的亚组，这些亚组主要根据AMKL相关标记物CD41的表达进行区分。我们的研究结果表明，胎儿肝细胞中NK5的表达会导致不同类型的白血病，其比例与儿科患者中观察到的相似。观察到的异质性和混合表型可能解释了一些携带NK5融合的患者在准确诊断白血病方面的困难。此外，这种方法可能有助于识别不同的NK5驱动的AML类型的分子或细胞基础。
