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ACUTE MYELOID LEUKEMIA

A novel lncRNA SNHG29 regulates EP300- related histone acetylation modification and inhibits FLT3-ITD AML development

Leukemia volume 37, pages 1421–1434 (2023)Cite this article

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Abstract

Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase-3 (FLT3) occur in up to 25% of acute myeloid leukemia (AML) patients and indicate a very poor prognosis. The role of long noncoding RNAs (lncRNAs) in FLT3-ITD AML progression remains unexplored. We identified a novel lncRNA, SNHG29, whose expression is specifically regulated by the FLT3-STAT5 signaling pathway and is abnormally down-regulated in FLT3-ITD AML cell lines. SNHG29 functions as a tumor suppressor, significantly inhibiting FLT3-ITD AML cell proliferation and decreasing sensitivity to cytarabine in vitro and in vivo models. Mechanistically, we demonstrated that SNHG29’s molecular mechanism is EP300-binding dependent and identified the EP300-interacting region of SNHG29. SNHG29 modulates genome-wide EP300 genomic binding, affecting EP300-mediated histone modification and consequently influencing the expression of varies downstream AML-associated genes. Our study uncovers a novel molecular mechanism for SNHG29 in mediating FLT3-ITD AML biological behaviors through epigenetic modification, suggesting that SNHG29 could be a potential therapeutic target for FLT3-ITD AML.

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Fig. 1: Expression of SNHG29 in FLT3-ITD and FLT3-WT AML cells.
Fig. 2: Molecular characteristics and expression regulation of SNHG29 in FLT3-ITD AML cells.
Fig. 3: SNHG29 is associated with proliferation and drug sensitivity of FLT3-ITD AML cells.
Fig. 4: SNHG29 inhibits growth and prompts drug resistance of FLT3-ITD AML cells in vivo.
Fig. 5: SNHG29 interacts with histone acetyltransferase EP300.
Fig. 6: SNHG29 modulates EP300 genomic binding.
Fig. 7: SNHG29 reduces EP300 enrichment in the promoter region of multiple leukemia-related genes.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Funding

This work was supported by the Fujian Provincial Health and Family Planning Commission Medical Innovation Fund (No.: 2018-CX-5 and 2019-CX-2), the Natural Science Foundation of Fujian Province, Fujian, China (No.: 2021J01389, 2020J011098, and 2022J0112), and the High-level Hospital Foster Grants from Fujian Provincial Hospital, Fujian Province, China (No.: 2019HSJJ15).

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Authors and Affiliations

  1. Department of Hematology-Oncology, Fujian Children’s Hospital; College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China

    Shan Liu

  2. Shengli Clinical Medical College of Fujian Medical University; Department of Hematology, Fujian Provincial Hospital, Fuzhou, Fujian, China

    Jie Zhou, Xiangling Ye, Danni Chen, Weimin Chen, Biyun Chen & Jin Shang

  3. Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China

    Yaobin Lin

  4. Shengli Clinical Medical College of Fujian Medical University; Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian, China

    Zhizhong Chen

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  1. Shan Liu
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Contributions

SJ and LS conceptualized the study; SJ, LS, ZJ, YXL, and CDN designed the experiments; LS, ZJ, LYB, and CZZ performed the experiments; SJ, LS, LYB, and ZJ produced the figures; LS and SJ wrote the original manuscript; SJ and CWM reviewed and edited the manuscript; SJ, LS, and CBY were responsible for funding application; SJ provided supervision. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Jin Shang.

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Liu, S., Zhou, J., Ye, X. et al. A novel lncRNA SNHG29 regulates EP300- related histone acetylation modification and inhibits FLT3-ITD AML development. Leukemia 37, 1421–1434 (2023). https://doi.org/10.1038/s41375-023-01923-y

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