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Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype

Starczynowski, Daniel T, Kuchenbauer, Florian, Argiropoulos, Bob, Sung, Sandy, Morin, Ryan, Muranyi, Andrew, Hirst, Martin, Hogge, Donna, Marra, Marco, Wells, Richard A, Buckstein, Rena, Lam, Wan, Humphries, R Keith, Karsan, Aly·2010·Nature Medicine
DOI 10.1038/nm.2054
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Abstract

5q- syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acute myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q- syndrome.

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  • miR-146a plays an important role not only in inhibition of proinflammatory signaling or proliferation, but also in directing an early, evolutionarily conserved differentiation program to promote development of macrophages in both embryos and adults.

    “The combination of gain-and loss-of-function experiments in mice and zebrafish suggest that miR-146a plays an important role not only in inhibition of proinflammatory signaling or proliferation, 16,17,19 but also in directing an early, evolutionarily conserved differentiation program to promote the development of macrophages in both embryos and adults.”

    From Macrophage development from HSCs requires PU.1-coordinated microRNA expression (2011) · cites this paper as [19]

  • Loss of expression of miR-146a, together with miR-145 loss, is implicated in the pathology of 5q- myelodysplastic syndrome, indicating a potential role as a tumor suppressor.

    “Loss of expression of miR-146a, together with miR-145 loss, was implicated in the pathology of the 5qϪ myelodysplastic syndrome, 19 indicating its potential role as a tumor suppressor.”

    From Macrophage development from HSCs requires PU.1-coordinated microRNA expression (2011) · cites this paper as [19]

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Research works printed but not linked: 48

  1. Corey, S.J. et al. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat. Rev. Cancer 7, 118–129 (2007). · DOI
  2. Nilsson, L. et al. Isolation and characterization of hematopoietic progenitor/stem cells in 5q–deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood 96, 2012–2021 (2000). · DOI
  3. Nilsson, L. et al. The molecular signature of MDS stem cells supports a stem-cell origin of 5q myelodysplastic syndromes. Blood 110, 3005–3014 (2007). · DOI
  4. Thanopoulou, E. et al. Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome. Blood 103, 4285–4293 (2004). · DOI
  5. Nimer, S.D. Myelodysplastic syndromes. Blood 111, 4841–4851 (2008). · DOI
  6. Li, X., Bryant, C.E. & Deeg, H.J. Simultaneous demonstration of clonal chromosome abnormalities and apoptosis in individual marrow cells in myelodysplastic syndrome. Int. J. Hematol. 80, 140–145 (2004). · DOI
  7. Giagounidis, A.A., Germing, U. & Aul, C. Biological and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin. Cancer Res. 12, 5–10 (2006). · DOI
  8. Boultwood, J. et al. Narrowing and genomic annotation of the commonly deleted region of the 5q– syndrome. Blood 99, 4638–4641 (2002). · DOI
  9. Martíinez-Ramirez, A. et al. Analysis of myelodysplastic syndromes with complex karyotypes by high-resolution comparative genomic hybridization and subtelomeric CGH array. Genes Chromosom. Cancer 42, 287–298 (2005). · DOI
  10. Wang, L. et al. Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays. Haematologica 93, 994–1000 (2008). · DOI
  11. Ebert, B.L. et al. Identification of RPS14 as a 5q– syndrome gene by RNA interference screen. Nature 451, 335–339 (2008). · DOI
  12. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism and function. Cell 116, 281–297 (2004). · DOI
  13. Ebert, M.S., Neilson, J.R. & Sharp, P.A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat. Methods 4, 721–726 (2007). · DOI · Paper page
  14. Gentner, B. et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nat. Methods 6, 63–66 (2009). · DOI
  15. Bigoni, R. et al. Multilineage involvement in the 5q– syndrome: a fluorescent in situ hybridization study on bone marrow smears. Haematologica 86, 375–381 (2001).
  16. Kroef, M.J. et al. Mosaicism of the 5q deletion as assessed by interphase FISH is a common phenomenon in MDS and restricted to myeloid cells. Leukemia 11, 519–523 (1997). · DOI
  17. Lewis, B.P., Shih, I.H., Jones-Rhoades, M.W., Bartel, D.P. & Burge, C.B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003). · DOI · Paper page
  18. Lamothe, B. et al. Site-specific Lys-63-linked tumor necrosis factor receptor–associated factor 6 auto-ubiquitination is a critical determinant of I κ B kinase activation. J. Biol. Chem. 282, 4102–4112 (2007). · DOI
  19. Mansell, A., Brint, E., Gould, J.A., O'Neill, L.A. & Hertzog, P.J. Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-κB activation by Toll-like receptor (TLR)-2 and TLR4. J. Biol. Chem. 279, 37227–37230 (2004). · DOI
  20. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001). · DOI · Paper page
  21. Nimer, S.D. Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. J. Clin. Oncol. 24, 2576–2582 (2006). · DOI
  22. Kishimoto, T. Interleukin-6: from basic science to medicine—40 years in immunology. Annu. Rev. Immunol. 23, 1–21 (2005). · DOI
  23. Garzon, R. et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111, 3183–3189 (2008). · DOI
  24. Marcucci, G. et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 358, 1919–1928 (2008). · DOI
  25. Takada, S. et al. MicroRNA expression profiles of human leukemias. Leukemia 22, 1274–1278 (2008). · DOI
  26. Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317, 124–127 (2007). · DOI
  27. Bhaumik, D. et al. Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells. Oncogene 27, 5643–5647 (2008). · DOI
  28. Chen, H. et al. Interference with nuclear factor κ B and c-Jun NH2-terminal kinase signaling by TRAF6C small interfering RNA inhibits myeloma cell proliferation and enhances apoptosis. Oncogene 25, 6520–6527 (2006). · DOI
  29. Maratheftis, C.I., Andreakos, E., Moutsopoulos, H.M. & Voulgarelis, M. Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes. Clin. Cancer Res. 13, 1154–1160 (2007). · DOI
  30. Hofmann, W.K. et al. Characterization of gene expression of CD34+ cells from normal and myelodysplastic bone marrow. Blood 100, 3553–3560 (2002). · DOI
  31. Gondek, L.P. et al. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD and MDS-derived AML. Blood 111, 1534–1542 (2008). · DOI
  32. Starczynowski, D.T. et al. High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood 112, 3412–3424 (2008). · DOI
  33. Garzon, R. et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc. Natl. Acad. Sci. USA 105, 3945–3950 (2008). · DOI
  34. Garzon, R. et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111, 3183–3189 (2008). · DOI
  35. Jongen-Lavrencic, M., Sun, S.M., Dijkstra, M.K., Valk, P.J. & Lowenberg, B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 111, 5078–5085 (2008). · DOI
  36. Li, Z. et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc. Natl. Acad. Sci. USA 105, 15535–15540 (2008). · DOI
  37. Takada, S. et al. MicroRNA expression profiles of human leukemias. Leukemia 22, 1274–1278 (2008). · DOI
  38. Hast, R., Eriksson, M., Widell, S., Arvidsson, I. & Bemell, P. Neutrophil dysplasia is not a specific feature of the abnormal chromosomal clone in myelodysplastic syndromes. Leuk. Res. 23, 579–584 (1999). · DOI
  39. Herold, M., Schmalzl, F. & Zwierzina, H. Increased serum interleukin 6 levels in patients with myelodysplastic syndromes. Leuk. Res. 16, 585–588 (1992). · DOI
  40. Verhoef, G.E. et al. Measurement of serum cytokine levels in patients with myelodysplastic syndromes. Leukemia 6, 1268–1272 (1992).
  41. Hsu, H.C. et al. Circulating levels of thrombopoietic and inflammatory cytokines in patients with acute myeloblastic leukemia and myelodysplastic syndrome. Oncology 63, 64–69 (2002). · DOI
  42. Brandt, S.J., Bodine, D.M., Dunbar, C.E. & Nienhuis, A.W. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J. Clin. Invest. 86, 592–599 (1990). · DOI · Paper page
  43. Hawley, R.G., Fong, A.Z., Burns, B.F. & Hawley, T.S. Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus. J. Exp. Med. 176, 1149–1163 (1992). · DOI
  44. Corral, L.G. et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J. Immunol. 163, 380–386 (1999). · DOI
  45. Nagai, Y. et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24, 801–812 (2006). · DOI
  46. Tang, M. et al. TAK1 is required for the survival of hematopoietic cells and hepatocytes in mice. J. Exp. Med. 205, 1611–1619 (2008). · DOI
  47. Antonchuk, J., Sauvageau, G. & Humphries, R.K. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Exp. Hematol. 29, 1125–1134 (2001). · DOI
  48. Larrivée, B., Pollet, I. & Karsan, A. Activation of vascular endothelial growth factor receptor-2 in bone marrow leads to accumulation of myeloid cells: role of granulocyte-macrophage colony-stimulating factor. J. Immunol. 175, 3015–3024 (2005). · DOI

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Metadata

Authors
Starczynowski, D. T., Kuchenbauer, F., Argiropoulos, B., Sung, S., Morin, R., Muranyi, A., Hirst, M., Hogge, D., Marra, M., Wells, R. A., Buckstein, R., Lam, W., Humphries, R. K., & Karsan, A.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2009-11-08
Volume
16
Issue
1
Pages
49-58
ISSN
  • 1078-8956
  • 1546-170X
DOI
10.1038/nm.2054
Cited by
577
References
1
Language
en
Licence
www.springer.com/tdm (tdm)

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