TIF1β/KAP1/TRIM28, a chromatin modulator, both represses and activates the transcription of genes in normal and malignant cells. Analyses of datasets on leukemia patients revealed that the expression level of TIF1β was increased in patients with chronic myeloid leukemia at the blast crisis and acute myeloid leukemia. We generated a BCR::ABL1 conditional knock-in (KI) mouse model, which developed aggressive myeloid leukemia, and demonstrated that the deletion of the Tif1β gene inhibited the progression of myeloid leukemia and showed longer survival than that in BCR::ABL1 KI mice, suggesting that Tif1β drove the progression of BCR::ABL1-induced leukemia. In addition, the deletion of Tif1β sensitized BCR::ABL1 KI leukemic cells to dasatinib. The deletion of Tif1β decreased the expression levels of TIF1β-target genes and chromatin accessibility peaks enriched with the Fosl1-binding motif in BCR::ABL1 KI stem cells. TIF1β directly bound to the promoters of proliferation genes, such as FOSL1, in human BCR::ABL1 cells, in which TIF1β and FOSL1 bound to adjacent regions of chromatin. Since the expression of Fosl1 was critical for the enhanced growth of BCR::ABL1 KI cells, Tif1β and Fosl1 interacted to activate the leukemic transcriptional program in and cellular function of BCR::ABL1 KI stem cells and drove the progression of myeloid leukemia.

TIF1β/KAP1/TRIM28 是一种染色质调节剂，可抑制和激活正常和恶性细胞中的基因转录。对白血病患者数据集的分析显示，慢性粒细胞白血病急变期和急性粒细胞白血病患者的TIF1β表达水平升高。我们构建了BCR::ABL1条件敲入 (KI) 小鼠模型，该模型发展为侵袭性髓系白血病，并证明Tif1β基因的删除可抑制髓系白血病的进展，并且比BCR::ABL1 KI 的生存期更长小鼠，表明Tif1β驱动了BCR::ABL1诱导的白血病的进展。此外，Tif1β的缺失使BCR::ABL1 KI 白血病细胞对达沙替尼敏感。 Tif1β的缺失降低了BCR::ABL1 KI 干细胞中 TIF1β 靶基因的表达水平和富含 Fosl1 结合基序的染色质可及性峰。在人BCR::ABL1细胞中， TIF1β 直接与增殖基因（例如FOSL1）的启动子结合，其中 TIF1β 和 FOSL1 与染色质的相邻区域结合。由于Fosl1的表达对于BCR::ABL1 KI 细胞的增强生长至关重要，因此 Tif1β 和 Fosl1 相互作用可激活BCR::ABL1 KI 干细胞中的白血病转录程序和细胞功能，并驱动髓系白血病的进展。