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ACUTE MYELOID LEUKEMIA

TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia

Leukemia (2024)Cite this article

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Abstract

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.

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Fig. 1: Increased expression of TIF1β in aggressive myeloid leukemia.
Fig. 2: Tif1β is critical for the progression and maintenance of BCR::ABL1-induced leukemia.
Fig. 3: The loss of Tif1β sensitized the BCR::ABL1 leukemic cells to the dasatinib treatment.
Fig. 4: Tif1β was required for BCR::ABL1-induced transcriptional reprogramming in HSCs.
Fig. 5: Tif1β was required for the BCR::ABL1-dependent remodeling of chromatin in stem cells.
Fig. 6: Fosl1 was required for the enhanced cell growth of BCR::ABL1-expressing myeloid leukemia.

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Data availability

Sequencing data that support the results of the present study have been deposited in DDBJ (https://ddbj.nig.ac.jp/search/en) under the accession numbers DRA015122, DRA015123, and DRA015124 for RNA-seq, ChIP-seq, and ATAC-seq, respectively.

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Acknowledgements

The authors thank Dr. Atsushi Iwama, Dr. Naoto Yamaguchi, Mr. Shinji Kudoh, and Dr. Takaaki Ito for their help and Dr. Florence Cammas for Tif1βflox/flox mice. This work was supported in part by grants from the Yasuda Medical Foundation (to GS), the Kobayashi Foundation for Cancer Research (to GS), the SENSHIN Medical Research Foundation (to GS), the Takeda Science Foundation (to MM and GS), the Japanese Society of Hematology (to GS), Grants-in-Aid for Scientific Research (18H02842, 21H02952, 21K06870 (to GS), 15K19545 (to SK), and 20K17383 (to MM)) and a Grant-in-Aid for JSPS Fellows (22J40054 to MM) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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Authors and Affiliations

  1. Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

    Mariko Morii, Sho Kubota, Mihoko Iimori, Takako Yokomizo-Nakano, Ai Hamashima, Jie Bai & Goro Sashida

  2. Gastrointestinal Cancer Biology, International Research Center of Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan

    Akiho Nishimura

  3. Department of Biomedical Laboratory Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan

    Masayoshi Tasaki

  4. Department of Amyloidosis Research, Nagasaki International University, Sasebo, Japan

    Yukio Ando

  5. Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan

    Kimi Araki

  6. Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan

    Kimi Araki

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Contributions

MM performed experiments, analyzed and interpreted data, and wrote the manuscript; SK performed experiments and analyzed data; MI, TYN, AH, JB, AN and MT performed experiments; YA provided reagents; KA performed experiments and provided reagents; GS designed the study, analyzed and interpreted data, and wrote the manuscript; All authors reviewed the manuscript.

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Correspondence to Goro Sashida.

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Morii, M., Kubota, S., Iimori, M. et al. TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia. Leukemia (2024). https://doi.org/10.1038/s41375-024-02276-w

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