组蛋白去甲基化酶KDM3B的缺失与髓系白血病发病密切相关，其确切的分子机制及表观遗传调控机制尚不清楚。本项目前期在急性早幼粒细胞白血病（APL）细胞NB4中发现KDM3B染色质结合区域显著富集转录因子CTCF模体，且二者共定位于细胞核内。干扰KDM3B表达后，APL特异融合蛋白PML-RARα表达量升高且细胞分化能力下降，组蛋白H3K9me1/me2整体修饰水平发生改变及染色质开放性增加。前期研究结果提示KDM3B可能协同CTCF形成信号轴参与调控APL细胞分化。为验证该假说，本研究拟从以下方面进行验证：1）明确KDM3B和CTCF的相互作用；2）确定KDM3B-CTCF轴在NB4细胞中的生物学功能；3）证实KDM3B-CTCF轴与PML-RARα的调控关系。这一科学假说的证实从KDM3B-CTCF轴的新视角阐释APL细胞分化调控机制，进而为APL的治疗提供新的理论基础和研究思路。

Deletion or loss of Histone demethylase KDM3B is closely related with myeloid leukemia. However, the detailed molecular and epigenetic mechanisms still need to be explored. Our preliminary experiments showed canonical CTCF motif was significantly enriched in regions marked by KDM3B occupancy by ChIP-seq technology and KDM3B co-localized in the nucleus with CTCF. In addition, we found that knock-down of KDM3B by shRNA increased the expression of acute promyelocytic leukemia (APL) specific PML-RARα fusion protein and repressed leukemia cell differentiation in APL cell line NB4. KDM3B silencing altered the global distribution of H3K9me1/me2 and increase the chromatin accessibility. Based on the preliminary research, we proposed a hypothesis that KDM3B-CTCF signaling axis could regulate the APL cell differentiation. In this project, we will undertake the strategies of cellular function research and high-throughput sequencing to validate the hypothesis, (1) to confirm that KDM3B interact with CTCF in APL, (2) to identify the biological function of KDM3B-CTCF signaling axis in NB4 cells by loss- and gain-of-function experiments, (3) to test and verify the regulatory relationship between KDM3B-CTCF signaling axis and PML-RARα. Our study will.provide novel insights into understanding of KDM3B-CTCF signaling axis in the regulation of APL progression, and will provide theoretical and experimental data for the treatment regimens and target therapy of APL.