Jmjd1c is dispensable for healthy adult hematopoiesis and Jak2V617F-driven myeloproliferative disease initiation in mice
Jmjd1c is dispensable for healthy adult hematopoiesis and Jak2V617F-driven myeloproliferative disease initiation in mice
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DOI：
10.1371/journal.pone.0228362
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发表时间：
2020-02-04
期刊：
影响因子：
3.7
通讯作者：
Jutzi, Jonas Samuel
中科院分区：
文献类型：
--
作者：
Staehle, Hans F.;Heinemann, Johannes;Jutzi, Jonas Samuel
组蛋白去甲基化酶JMJD 1C在骨髓增生性肿瘤（MPN）患者中过表达，并与MLL-AF 9和HOXA 9驱动的白血病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，JMJD 1C因此成为一个潜在的靶标。耗尽Jmjd 1c表达显着降低了MPN细胞系中的非依赖于精氨酸的生长，表明Jmjd 1c在MPN疾病维持中的作用。在这里，我们研究了脱甲基酶在MPN疾病发生中的潜在作用。我们将Cre诱导的JAK 2（V617 F）突变引入Jmjd 1c敲除小鼠。我们发现，Jmjd 1c是不稳定的，无论是健康的造血，以及JAK 2（V617 F）驱动的MPN疾病的启动。jmjd 1c基因敲除小鼠的外周血成分没有明显变化。同样地，将JAK 2（V617 F）引入Jmjd 1c（-/-）小鼠中导致与Jmjd 1c wt背景中的JAK 2（V617 F）相似的MPN表型。这表明JMJD 1C在白血病干细胞和MPN中的作用之间存在差异。在后者中，含有JMJC结构域的家族成员可能发挥冗余作用，补偿单个蛋白质的损失。
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 JAK2(V617F) mutation into Jmjd1c knockout mice. We show that Jmjd1c is dispensable, both for healthy hematopoiesis as well as for JAK2(V617F)-driven MPN disease initiation. Jmjd1c knockout mice did not show any significant changes in peripheral blood composition. Likewise, introduction of JAK2(V617F) into Jmjd1c(-/-) mice led to a similar MPN phenotype as JAK2(V617F) 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.