Division of Molecular Hematology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Baden-Württemberg, Germany.
PLoS One. 2020 Feb 4;15(2):e0228362. doi: 10.1371/journal.pone.0228362. eCollection 2020.
The histone demethylase JMJD1C is overexpressed in patients with myeloproliferative neoplasms (MPNs) and has been implicated in leukemic stem cell function of MLL-AF9 and HOXA9-driven leukemia. In the emerging field of histone demethylase inhibitors, JMJD1C therefore became a potential target. Depletion of Jmjd1c expression significantly reduced cytokine-independent growth in an MPN cell line, indicating a role for JMJD1C in MPN disease maintenance. Here, we investigated a potential role for the demethylase in MPN disease initiation. We introduced a Cre-inducible JAK2V617F mutation into Jmjd1c knockout mice. We show that Jmjd1c is dispensable, both for healthy hematopoiesis as well as for JAK2V617F-driven MPN disease initiation. Jmjd1c knockout mice did not show any significant changes in peripheral blood composition. Likewise, introduction of JAK2V617F into Jmjd1c-/- mice led to a similar MPN phenotype as JAK2V617F in a Jmjd1c wt background. This indicates that there is a difference between the role of JMJD1C in leukemic stem cells and in MPN. In the latter, JMJC domain-containing family members may serve redundant roles, compensating for the loss of individual proteins.
组蛋白去甲基化酶 JMJD1C 在骨髓增生性肿瘤（MPN）患者中过表达，并与 MLL-AF9 和 HOXA9 驱动的白血病中的白血病干细胞功能有关。在新兴的组蛋白去甲基化酶抑制剂领域，JMJD1C 因此成为一个潜在的靶点。Jmjd1c 表达的耗竭显著降低了 MPN 细胞系中细胞因子非依赖性生长，表明 JMJD1C 在 MPN 疾病维持中发挥作用。在这里，我们研究了去甲基酶在 MPN 疾病起始中的潜在作用。我们将 Cre 诱导的 JAK2V617F 突变引入 Jmjd1c 敲除小鼠。我们表明，JMJD1C 对于健康造血以及 JAK2V617F 驱动的 MPN 疾病的起始都是可有可无的。Jmjd1c 敲除小鼠在外周血组成中没有显示出任何显著变化。同样，将 JAK2V617F 引入 Jmjd1c-/- 小鼠中导致与 Jmjd1c wt 背景中的 JAK2V617F 相似的 MPN 表型。这表明 JMJD1C 在白血病干细胞和 MPN 中的作用不同。在后一种情况下，JMJC 结构域包含家族成员可能发挥冗余作用，补偿单个蛋白质的缺失。
