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Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

Leukemia volume 31, pages 491–495 (2017)Cite this article

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A Corrigendum to this article was published on 07 April 2017

Interstitial deletion of a single copy of chromosome 5q is the most frequent cytogenetic alteration in myelodysplastic syndromes (MDS), which results in reduced dosage of numerous genes. Moreover, the extent of the 5q deletion determines disease severity,1 suggesting cooperation between deleted genes in the proximal and distal regions of del(5q). Although the contribution of individual genes to the pathogenesis of del(5q) MDS has been investigated, less is known about the epistatic interactions and/or cooperation between neighboring deleted genes. Deletion of TRAF-interacting protein with forkhead-associated domain B (TIFAB) and miR-146a, two haploinsufficient genes in del(5q) MDS, has been previously reported to activate the Toll-like receptor (TLR) signaling cascade in hematopoietic stem/progenitor cells (HSPC) by increasing TRAF6 protein stability and mRNA translation, respectively.2 To investigate the epistasis of TIFAB and miR-146a, we generated a mouse model in which Tifab and miR-146a were simultaneously deleted (Tifab−/−; miR-146a−/−, dKO). Herein, we report that combined hematopoietic-specific deletion of Tifab and miR-146a results in more rapid and severe cytopenia, and progression to a fatal bone marrow (BM) failure-like disease as compared with Tifab- or miR-146a-deficiency alone. HSPC from Tifab−/−, miR-146a−/− and dKO mice exhibit enrichment of gene regulatory networks associated with innate immune signaling. Moreover, a subset of the differentially expressed genes is controlled synergistically following deletion of Tifab and miR-146a. Notably, nearly half of these defined synergy response genes identified in the mouse models were aberrantly expressed in del(5q) MDS HSPC when TIFAB (5q31) and miR-146a (5q33.3) were both deleted. Thus, synergistic control of gene expression following deletion of epistatic haploinsufficient genes in del(5q) MDS may be an underlying mechanism of the diseased state.

TIFAB resides within the proximal commonly-deleted region on band 5q31.1, and belongs to a family of forkhead-associated domain proteins. TIFAB is a gene that is deleted in nearly all reported cases of del(5q) MDS and acute myeloid leukemia (AML).2, 3 As expected, TIFAB expression is significantly lower in CD34+ and BM mononuclear (MNC) cells isolated from MDS patients with del(5q) as compared with cells from MDS patients diploid at chr 5q. Recently we have shown that hematopoietic-specific deletion of Tifab results in progressive BM and blood defects, including aberrant HSPC proportions, altered myeloid differentiation and progressive cytopenia.2 Approximately 10% of mice transplanted with Tifab KO HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. Gene expression analysis of Tifab KO lineage-Sca1+cKit+ (LSK) cells identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. We also reported that TIFAB forms a complex with TRAF6, and reduces TRAF6 protein stability. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced MDS/AML cell viability.2 In a separate study, TIFAB was identified by a retroviral insertional mutagenesis screen as a target in del(5q) myeloid neoplasms.3

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References

  1. Jerez A, Gondek LP, Jankowska AM, Makishima H, Przychodzen B, Tiu RV et al. Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited. J Clin Oncol 2012; 30: 1343–1349.

    Article  Google Scholar 

  2. Varney ME, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N et al. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med 2015; 212: 1967–1985.

    Article  CAS  Google Scholar 

  3. Stoddart A, Qian Z, Fernald AA, Bergerson RJ, Wang J, Karrison T et al. Retroviral insertional mutagenesis identifies the del(5q) genes, CXXC5, TIFAB and ETF1, as well as the Wnt pathway, as potential targets in del(5q) myeloid neoplasms. Haematologica 2016; 101: e232–e236.

    Article  CAS  Google Scholar 

  4. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 2011; 208: 1189–1201.

    Article  CAS  Google Scholar 

  5. Fang J, Barker B, Bolanos L, Liu X, Jerez A, Makishima H et al. Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-kappaB gene network. Cell Rep 2014; 8: 1328–1338.

    Article  CAS  Google Scholar 

  6. Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med 2010; 16: 49–58.

    Article  CAS  Google Scholar 

  7. Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM, Baltimore D . NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci USA 2011; 108: 9184–9189.

    Article  CAS  Google Scholar 

  8. Zhao JL, Rao DS, O'Connell RM, Garcia-Flores Y, Baltimore D . MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice. eLife 2013; 2: e00537.

    Article  Google Scholar 

  9. McMurray HR, Sampson ER, Compitello G, Kinsey C, Newman L, Smith B et al. Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 2008; 453: 1112–1116.

    Article  CAS  Google Scholar 

  10. Pellagatti A, Cazzola M, Giagounidis A, Perry J, Malcovati L, Della Porta MG et al. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 2010; 24: 756–764.

    Article  CAS  Google Scholar 

  11. Taganov KD, Boldin MP, Chang KJ, Baltimore D . NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006; 103: 12481–12486.

    Article  CAS  Google Scholar 

  12. Chen J, Bardes EE, Aronow BJ, Jegga AG . ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 2009; 37: W305–W311.

    Article  CAS  Google Scholar 

  13. Komurov K, Dursun S, Erdin S, Ram PT . NetWalker: a contextual network analysis tool for functional genomics. BMC Genom 2012; 13: 282.

    Article  Google Scholar 

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Acknowledgements

This work was supported by Cincinnati Children’s Hospital Research Foundation, American Society of Hematology (ASH), National Institute of Health (RO1HL111103) and Department of Defense grants to DTS. DTS is a Leukemia and Lymphoma Scholar. The umbilical cord CD34+ samples were received through the Normal Donor Repository in the Translational Core Laboratory at Cincinnati Children’s Research Foundation, which is supported through the NIDDK Center’s of Excellence in Experimental Hematology (P30DK090971). We thank the Mt. Auburn Ob-Gyn associates and delivery nursing staff at Christ Hospital (Cincinnati, OH) for collecting cord blood (CD34+) samples from normal deliveries. We thank Jeff Bailey and Victoria Summey for assistance with transplantations and xenotransplantations (Comprehensive Mouse and Cancer Core at CCHMC). We would also like to thank the pathology core at CCHMC for analysis of mouse tissues.

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Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    M E Varney, K Choi, L Bolanos, S Christie, J Fang & D T Starczynowski

  2. Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    L H Grimes

  3. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    J P Maciejewski

  4. Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan

    J-I Inoue

  5. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    D T Starczynowski

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  1. M E Varney
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Correspondence to D T Starczynowski.

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Varney, M., Choi, K., Bolanos, L. et al. Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome. Leukemia 31, 491–495 (2017). https://doi.org/10.1038/leu.2016.276

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