ChIP-seq of TIF1b modulates the chromatin accessibility to regulate the self-renewal and differentiation of leukemic stem cells

Chronic myeloid leukemia (CML), characterized by expression of p210-BCR-ABL, is a clonal myeloproliferative disease initiated by malignant transformation of hematopoietic stem cells (HSC). Recently, high expression of TIF1b/TRIM28/KAP1 was correlated with poor prognosis in patients with various types of cancer, but the role of Tif1b in myeloid leukemia is unclear. To determine whether TIF1b promoted the development of BCR-ABL-induced myeloid leukemia in vivo, we generated BCR-ABL;Tif1bf/f;Cre-ERT2 compound mice by crossing Rosa26 locus BCR-ABL conditional knock-in mice and Tif1bf/f;Cre-ERT2 conditional KO mice. We transplanted BM cells isolated from Cre-ERT2 (WT), Tif1bf/f;Cre-ERT2 (Tif1b KO), BCR-ABL;Cre-ERT2 (BCR-ABL), and BCR-ABL;Tif1bf/f;Cre-ERT2 (BCR-ABL;Tif1b KO) mice into lethally irradiated CD45.1+ WT recipient mice, and injected tamoxifen 4 weeks after BM transplantation. To elucidate the mechanisms underlying the impaired development of leukemia in BCR-ABL;Tif1b KO mice, we performed RNA sequencing analyses of HSCs isolated from WT, Tif1b KO, BCR-ABL, BCR-ABL;Tif1b KO mice.

慢性髓系白血病（Chronic myeloid leukemia, CML）以p210-BCR-ABL的表达为特征，是一类由造血干细胞（hematopoietic stem cells, HSC）恶性转化引发的克隆性骨髓增殖性疾病。近期研究表明，TIF1b/TRIM28/KAP1高表达与多种癌症患者的不良预后密切相关，但Tif1b在髓系白血病中的作用仍未明确。为探究TIF1b是否可在体内促进BCR-ABL诱导的髓系白血病发生，本研究通过将罗莎26（Rosa26）位点BCR-ABL条件性敲入小鼠与Tif1bf/f;Cre-ERT2条件性敲除小鼠杂交，成功构建了BCR-ABL;Tif1bf/f;Cre-ERT2复合基因型小鼠。我们分别从Cre-ERT2（野生型，WT）、Tif1bf/f;Cre-ERT2（Tif1b敲除，Tif1b KO）、BCR-ABL;Cre-ERT2（BCR-ABL）以及BCR-ABL;Tif1bf/f;Cre-ERT2（BCR-ABL;Tif1b敲除，BCR-ABL;Tif1b KO）小鼠中分离骨髓细胞，将其移植至经致死剂量照射的CD45.1+野生型受体小鼠体内，并于骨髓移植后4周注射他莫昔芬。为阐明BCR-ABL;Tif1b敲除小鼠白血病发生受损的潜在机制，我们对从野生型、Tif1b敲除、BCR-ABL及BCR-ABL;Tif1b敲除小鼠中分离得到的造血干细胞开展了RNA测序分析。