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Oncogenes, Fusion Genes and Tumor Suppressor Genes

The leukemogenicity of Hoxa9 depends on alternative splicing

Leukemia volume 28, pages 1838–1843 (2014)Cite this article

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Abstract

Although the transforming potential of Hox genes is known for a long time, it is not precisely understood to which extent splicing is important for the leukemogenicity of this gene family. To test this for Hoxa9, we compared the leukemogenic potential of the wild-type Hoxa9, which undergoes natural splicing, with a full-length Hoxa9 construct, which was engineered to prevent natural splicing (Hoxa9FLim). Inability to undergo splicing significantly reduced in vivo leukemogenicity compared to Hoxa9-wild-typed. Importantly, Hoxa9FLim could compensate for the reduced oncogenicity by collaborating with the natural splice variant Hoxa9T, as co-expression of Hoxa9T and Hoxa9FLim induced acute myeloid leukemia (AML) after a comparable latency time as wild-type Hoxa9. Hoxa9T on its own induced AML after a similar latency as Hoxa9FLim, despite its inability to bind DNA. These data assign splicing a central task in Hox gene mediated leukemogenesis and suggest an important role of homeodomain-less splice variants in hematological neoplasms.

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References

  1. Hahn CN, Scott HS . Spliceosome mutations in hematopoietic malignancies. Nat Genet 2012; 44: 9–10.

    Article  CAS  Google Scholar 

  2. Talavera D, Orozco M, de la Cruz X . Alternative splicing of transcription factors' genes: beyond the increase of proteome diversity. Comp Funct Genomics 2009; 2009: 905894.

    Article  Google Scholar 

  3. Reed HC, Hoare T, Thomsen S, Weaver TA, White RA, Akam M et al. Alternative splicing modulates Ubx protein function in Drosophila melanogaster. Genetics 2010; 184: 745–758.

    Article  CAS  Google Scholar 

  4. Lawrence HJ, Helgason CD, Sauvageau G, Fong S, Izon DJ, Humphries RK et al. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood 1997; 89: 1922–1930.

    CAS  Google Scholar 

  5. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999; 286: 531–537.

    Article  CAS  Google Scholar 

  6. Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G . Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol 2001; 21: 224–234.

    Article  CAS  Google Scholar 

  7. Rawat VP, Humphries RK, Buske C . Beyond HOX: the role of ParaHox genes in normal and malignant hematopoiesis. Blood 2012; 120: 519–527.

    Article  CAS  Google Scholar 

  8. Breitinger C, Maethner E, Garcia-Cuellar MP, Slany RK . The homeodomain region controls the phenotype of HOX-induced murine leukemia. Blood 2012; 120: 4018–4027.

    Article  CAS  Google Scholar 

  9. Fujimoto S, Araki K, Chisaka O, Araki M, Takagi K, Yamamura K . Analysis of the murine Hoxa-9 cDNA: an alternatively spliced transcript encodes a truncated protein lacking the homeodomain. Gene 1998; 209: 77–85.

    Article  CAS  Google Scholar 

  10. Schessl C, Rawat VP, Cusan M, Deshpande A, Kohl TM, Rosten PM et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 2005; 115: 2159–2168.

    Article  CAS  Google Scholar 

  11. Dintilhac A, Bihan R, Guerrier D, Deschamps S, Pellerin I . A conserved non-homeodomain Hoxa9 isoform interacting with CBP is co-expressed with the 'typical' Hoxa9 protein during embryogenesis. Gene Expr Patterns 2004; 4: 215–222.

    Article  CAS  Google Scholar 

  12. Deshpande AJ, Cusan M, Rawat VP, Reuter H, Krause A, Pott C et al. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell 2006; 10: 363–374.

    Article  CAS  Google Scholar 

  13. Deshpande AJ, Rouhi A, Lin Y, Stadler C, Greif PA, Arseni N et al. The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice. Leukemia 2011; 25: 1718–1727.

    Article  CAS  Google Scholar 

  14. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.

    Article  Google Scholar 

  15. Williams GT, Farzaneh F . Are snoRNAs and snoRNA host genes new players in cancer? Nat Rev Cancer 2012; 12: 84–88.

    Article  CAS  Google Scholar 

  16. Bazeley PS, Shepelev V, Talebizadeh Z, Butler MG, Fedorova L, Filatov V et al. snoTARGET shows that human orphan snoRNA targets locate close to alternative splice junctions. Gene 2008; 408: 172–179.

    Article  CAS  Google Scholar 

  17. He M, Chen P, Arnovitz S, Li Y, Huang H, Neilly MB et al. Two isoforms of HOXA9 function differently but work synergistically in human MLL-rearranged leukemia. Blood Cells Mol Dis 2012; 49: 102–106.

    Article  CAS  Google Scholar 

  18. Bach C, Buhl S, Mueller D, Garcia-Cuellar MP, Maethner E, Slany RK . Leukemogenic transformation by HOXA cluster genes. Blood 2010; 115: 2910–2918.

    Article  CAS  Google Scholar 

  19. Shen WF, Detmer K, Simonitch-Eason TA, Lawrence HJ, Largman C . Alternative splicing of the HOX 2.2 homeobox gene in human hematopoietic cells and murine embryonic and adult tissues. Nucleic Acids Res 1991; 19: 539–545.

    Article  CAS  Google Scholar 

  20. Schnabel CA, Jacobs Y, Cleary ML . HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis. Oncogene 2000; 19: 608–616.

    Article  CAS  Google Scholar 

  21. Huang Y, Sitwala K, Bronstein J, Sanders D, Dandekar M, Collins C et al. Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood 2012; 119: 388–398.

    Article  CAS  Google Scholar 

  22. Fernandez CC, Gudas LJ . The truncated Hoxa1 protein interacts with Hoxa1 and Pbx1 in stem cells. J Cell Biochem 2009; 106: 427–443.

    Article  CAS  Google Scholar 

  23. Benson GV, Nguyen TH, Maas RL . The expression pattern of the murine Hoxa-10 gene and the sequence recognition of its homeodomain reveal specific properties of Abdominal B-like genes. Mol Cell Biol 1995; 15: 1591–1601.

    Article  CAS  Google Scholar 

  24. Noro B, Culi J, McKay DJ, Zhang W, Mann RS . Distinct functions of homeodomain-containing and homeodomain-less isoforms encoded by homothorax. Genes Dev 2006; 20: 1636–1650.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant of the Deutsche Krebshilfe (German Cancer Aid) (Project No 108438 to CB). We want to thank the Core Facility FACS, Ulm University and the team of the animal facility at Ulm University and at the Helmholtz Center Munich.

Author Contributions

CRS, NV, MAM, VPSR, KEE, AD, LB, BH and LQ-F performed research and KS, WH, KD, HD and MF-B provided patient samples and analyzed data. CB designed the research. CRS, NV and CB analyzed the data and wrote the manuscript.

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Author notes

  1. C R Stadler and N Vegi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany

    C R Stadler, K Spiekermann & W Hiddemann

  2. Clinical Cooperative Group ‘Pathogenesis of Acute Myeloid Leukemia’, Helmholtz Center Munich for Environmental Health, Munich, Germany

    C R Stadler, K Spiekermann & W Hiddemann

  3. Institute of Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany

    N Vegi, M A Mulaw, K E Edmaier, V P S Rawat & C Buske

  4. Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany

    A Dolnik, L Bullinger, K Döhner, H Döhner & M Feuring-Buske

  5. Department of Oncology and Hematology, Hospital Barmherzige Brüder, Regensburg, Germany

    B Heilmeier

  6. Institute of Pathology, University of Tübingen, Tübingen, Germany

    L Quintanilla-Fend

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  1. C R Stadler
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Correspondence to C Buske.

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Stadler, C., Vegi, N., Mulaw, M. et al. The leukemogenicity of Hoxa9 depends on alternative splicing. Leukemia 28, 1838–1843 (2014). https://doi.org/10.1038/leu.2014.74

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