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A comprehensive analysis of LMO2 pathogenic regulatory profile during T-lineage development and leukemic transformation

Abstract

LMO2 is a well-known leukemic proto-oncogene, its ectopic expression in T-lineage specifically initiates malignant transformation of immature T cells and ultimately causes the onset of acute T-lymphocytic leukemia (T-ALL) in both mouse models and human patients. In this study, we systematically explored the LMO2 performance on the profiles of transcriptome, DNA-binding and protein interactions during T-lineage development in the pre-leukemic stage. Our data indicated that large-scale transcriptional dysregulation caused by LMO2 primarily occurred in DN3 thymocytes, characterized by enriched upregulation of the target genes of typical LMO2 complex, RUNX, ETS and STATs, and ectopic LMO2 primarily targeted to RUNX motifs along with intensive interaction with RUNX1 and H3K4 methyltransferase component ASH2L in this stage. However, binding of LMO2 on specific motifs was largely reduced in the following DP and SP stages, along with gradually disappeared LMO2-RUNX1 and LMO2-ASH2L interactions and less alteration of certain transcriptional factor profiles. Moreover, LMO2 showed relatively less influence on cellular behavior of DN3 thymocyte whereas displayed more prominent effects in DP and SP stages, including promoting Notch signaling and cell cycles. These findings provide a high-resolution landscape of the pathogenic role of LMO2 during T-lineage development in molecular level, and may benefit further clinical investigations for LMO2-associated T-lineage malignancies.

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Fig. 1: Ectopic expression of LMO2 caused typical thymocyte development abnormality and leukemic phenotype in mice.
Fig. 2: Primary alteration of transcriptome features upon LMO2 ectopic expression in thymocytes.
Fig. 3: Time-course feature of transcriptome during thymocyte development and typical alterations upon LMO2 ectopic expression.
Fig. 4: DNA-binding profiles of LMO2 during T-lineage development suggested high preference of LMO2 on RUNX motifs specifically in DN3 thymocytes.
Fig. 5: RUNX1 was identified as a LMO2 direct binding target specifically in DN3 stage.
Fig. 6: H3K4 methyltransferase component ASH2L was identified as a novel partner of LMO2 in thymocytes.
Fig. 7: Expression characteristics of key transcriptional regulators and function overview of ectopic LMO2 during thymocyte development.

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Acknowledgements

This work is supported by the National Natural Science Foundation of China General Programs (No. 81772976).

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WWH performed the major experiment work; MYY performed part of the experiments, particularly the public data analysis; CYX performed part of the experiments, particularly the in vitro protein assays; YYH performed part of the biochemical experiments; WH was in charge of all flow-cytometry manipulations; YS provided the major bench sources for this study; SW designed the work and was in charge of all data integration and paper preparation.

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Correspondence to Wei Sun.

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Wang, W., Meng, Y., Chen, Y. et al. A comprehensive analysis of LMO2 pathogenic regulatory profile during T-lineage development and leukemic transformation. Oncogene 41, 4079–4090 (2022). https://doi.org/10.1038/s41388-022-02414-7

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