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

Oncogene volume 41, pages 4079–4090 (2022)Cite this article

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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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References

  1. Royer-Pokora B, Loos U, Ludwig WD. TTG-2 a new gene encoding a cysteine-rich protein with LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene. 1991;6:1887–93.

    CAS  PubMed  Google Scholar 

  2. Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH. The rhombotin family of cysteinerich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc Natl Acad Sci USA. 1991;88:4367–71.

    Article  CAS  Google Scholar 

  3. Larson RC, Fisch P, Larson TA, Lavenir I, Langford T, King G, et al. T cell tumours with disparate phenotype in mice transgenic for Rbtn-2. Oncogene. 1994;9:3675–81.

    CAS  PubMed  Google Scholar 

  4. McCormack MP, Young LF, Vasudevan S, de Graaf CA, Codrington R, Rabbitts TH, et al. The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte self-renewal. Science. 2010;327:879–83.

    Article  CAS  Google Scholar 

  5. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

    Article  CAS  Google Scholar 

  6. Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Investig. 2008;118:3143–50.

    Article  CAS  Google Scholar 

  7. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Investig. 2008;118:3132–42.

    Article  CAS  Google Scholar 

  8. Warren AJ, Colledge WH, Carlton MB, Evans MJ, Smith AJ, Rabbitts TH. The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell. 1994;78:45–57.

    Article  CAS  Google Scholar 

  9. Yamada Y, Warren AJ, Dobson C, Forster A, Pannell R, Rabbitts TH. The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc Natl Acad Sci USA. 1998;95:3890–5.

    Article  CAS  Google Scholar 

  10. Pike-Overzet K, de Ridder D, Weerkamp F, Baert MR, Verstegen MM, Brugman MH, et al. Ectopic retroviral expression of LMO2, but not IL2Rc, blocks human T-cell development. Leukemia. 2007;21:754–63.

    Article  CAS  Google Scholar 

  11. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1:75–87.

    Article  CAS  Google Scholar 

  12. Chambers J, Rabbitts TH. LMO2 at 25 years: a paradigm of chromosomal translocation proteins. Open Biol. 2015;5:150062.

    Article  Google Scholar 

  13. Smith S, Tripathi R, Goodings C, Cleveland S, Mathias E, Hardaway JA, et al. LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways. PLoS ONE. 2014;9:e85883.

    Article  Google Scholar 

  14. Cubedo E, Gentles AJ, Huang C, Natkunam Y, Bhatt S, Lu X, et al. Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma. Blood. 2012;119:5478–91.

    Article  CAS  Google Scholar 

  15. Sun W, Yang S, Shen W, Li H, Gao Y, Zhu TH. Identification of DeltaEF1 as a novel target that is negatively regulated by LMO2 in T-cell leukemia. Eur J Haematol. 2010;85:508–19.

    Article  CAS  Google Scholar 

  16. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med. 2004;350:1828–37.

    Article  CAS  Google Scholar 

  17. Natkunam Y, Zhao S, Mason DY, Chen J, Taidi B, Jones M, et al. The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. Blood. 2007;109:1636–42.

    Article  CAS  Google Scholar 

  18. Natkunam Y, Farinha P, Hsi ED, Hans CP, Tibshirani R, Sehn LH, et al. LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J Clin Oncol. 2008;26:447–54.

    Article  CAS  Google Scholar 

  19. Malumbres R, Fresquet V, Roman-Gomez J, Bobadilla M, Robles EF, Altobelli GG, et al. LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome. Haematologica. 2011;96:980–6.

    Article  Google Scholar 

  20. Parvin S, Ramirez-Labrada A, Aumann S, Lu X, Weich N, Santiago G, et al. LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL. Cancer Cell. 2019;36:237–49.

    Article  CAS  Google Scholar 

  21. Rothenberg EV. Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals. Immunity. 2007;26:690–702.

    Article  CAS  Google Scholar 

  22. McCormack MP, Forster A, Drynan L, Pannell R, Rabbitts TH. The LMO2 T-cell oncogene is activated via chromosomal translocations or retroviral insertion during gene therapy but has no mandatory role in normal T-cell development. Mol Cell Biol 2003;23:9003–13.

    Article  CAS  Google Scholar 

  23. Gao T, He B, Liu S, Zhu H, Tan K, Qian J. EnhancerAtlas: a resource for enhancer annotation and analysis in 105 human cell/tissue types. Bioinformatics. 2016;32:3543–51.

    Article  CAS  Google Scholar 

  24. Goode DK, Obier N, Vijayabaskar MS, Lie-A-Ling M, Lilly AJ, Hannah R, et al. Dynamic gene regulatory networks drive hematopoietic specification and differentiation. Dev Cell. 2016;36:572–87.

    Article  CAS  Google Scholar 

  25. Shin B, Hosokawa H, Romero-Wolf M, Zhou W, Masuhara K, Tobin VR, et al. Runx1 and Runx3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching. Proc Natl Acad Sci USA. 2021;118:e2019655118.

    Article  CAS  Google Scholar 

  26. Gao P, Chen C, Howell ED, Li Y, Tober J, Uzun Y, et al. Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells. Genes Dev. 2020;34:950–64.

    Article  CAS  Google Scholar 

  27. Hosokawa H, Ungerbäck J, Wang X, Matsumoto M, Nakayama KI, Cohen SM, et al. Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding. Immunity. 2018;48:1119–34.

    Article  CAS  Google Scholar 

  28. Wang W, Chen Y, Chang Y, Sun W. Biochemical feature of LMO2 interactome and LMO2 function prospect. Med Sci Monit Basic Res. 2020;26:e924421.

    Article  Google Scholar 

  29. Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007;26:2361–70.

    Article  CAS  Google Scholar 

  30. Zhang DE, Hetherington CJ, Meyers S, Rhoades KL, Larson CJ, Chen HM, et al. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Mol Cell Biol. 1996;16:1231–40.

    Article  CAS  Google Scholar 

  31. Wu C, Li J, Tian C, Shi W, Jiang H, Zhang Z, et al. Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis. Biochim Biophys Acta Mol Basis Dis. 2018;1864:2511–25.

    Article  CAS  Google Scholar 

  32. Sun W, Shen WW, Yang S, Hu F, Gao Y, Qiao YH, et al. Homo-binding character of LMO2 isoforms and their both synergic and antagonistic functions in regulating hematopoietic-related target genes. J Biomed Sci. 2010;17:22.

    Article  Google Scholar 

  33. Mao S, Frank RC, Zhang J, Miyazaki Y, Nimer SD. Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias. Mol Cell Biol. 1999;19:3635–44.

    Article  CAS  Google Scholar 

  34. Palii CG, Perez-Iratxeta C, Yao Z, Cao Y, Dai F, Davison J, et al. Differential genomic targeting of the transcription factor TAL1 in alternate haematopoietic lineages. EMBO J. 2011;30:494–509.

    Article  CAS  Google Scholar 

  35. Liu Y, Huang D, Wang Z, Wu C, Zhang Z, Wang D, et al. LMO2 attenuates tumor growth by targeting the Wnt signaling pathway in breast and colorectal cancer. Sci Rep. 2016;6:36050.

    Article  CAS  Google Scholar 

  36. Liu Y, Wang Z, Huang D, Wu C, Li H, Zhang X, et al. LMO2 promotes tumor cell invasion and metastasis in basal-type breast cancer by altering actin cytoskeleton remodeling. Oncotarget. 2017;8:9513–24.

    Article  Google Scholar 

  37. Liu Y, Wu C, Zhu T, Sun W. LMO2 enhances lamellipodia/filopodia formation in basal-type breast cancer cells by mediating ARP3-profilin1 interaction. Med Sci Monit. 2017;23:695–703.

    Article  CAS  Google Scholar 

  38. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

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Authors and Affiliations

  1. School of Medicine, Nankai University, Tianjin, China

    Wenhao Wang, Yingying Meng, Yaxin Chen, Yanhong Yu, Hang Wang, Shuang Yang & Wei Sun

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  1. Wenhao Wang
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Contributions

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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