MiR-143/145 Differentially Regulate Hematopoietic Stem and Progenitor Activity Through Suppression of Canonical TGFβ Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 22

PMID 29925839

Citations 24

Authors

Jeffrey Lam

Marion van den Bosch

Joanna Wegrzyn

Jeremy Parker

Rawa Ibrahim

Kate Slowski

Linda Chang

Sergio Martinez-Hoyer

Gianluigi Condorelli

Mark Boldin

Yu Deng

Patricia Umlandt

Megan Fuller

Aly Karsan

Affiliations

Soon will be listed here.

Abstract

Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor β (TGFβ) pathway as key targets of miR-143/145. Enforced expression of the TGFβ adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145 mice. Despite reduced HSC activity, older miR-143/145 and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFβ/DAB2 activation, and loss of these miRNAs creates a preleukemic state.

Citing Articles

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References

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Krivtsov A, Twomey D, Feng Z, Stubbs M, Wang Y, Faber J . Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006; 442(7104):818-22. DOI: 10.1038/nature04980. View

Nilsson L, Arvidsson I, Jacobsson B, Hellstrom-Lindberg E, Hast R, Jacobsen S . Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood. 2000; 96(6):2012-21. View

Liu Q, Wang M, Hu Y, Xing H, Chen X, Zhang Y . Significance of CD71 expression by flow cytometry in diagnosis of acute leukemia. Leuk Lymphoma. 2013; 55(4):892-8. DOI: 10.3109/10428194.2013.819100. View

Hocevar B, Smine A, Xu X, Howe P . The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J. 2001; 20(11):2789-801. PMC: 125498. DOI: 10.1093/emboj/20.11.2789. View

Starczynowski D, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A . Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2009; 16(1):49-58. DOI: 10.1038/nm.2054. View

Lewis B, Burge C, Bartel D . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120(1):15-20. DOI: 10.1016/j.cell.2004.12.035. View

Raza A, Galili N . The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes. Nat Rev Cancer. 2012; 12(12):849-59. DOI: 10.1038/nrc3321. View

Pang W, Pluvinage J, Price E, Sridhar K, Arber D, Greenberg P . Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci U S A. 2013; 110(8):3011-6. PMC: 3581956. DOI: 10.1073/pnas.1222861110. View

10.

Ye M, Zhang H, Yang H, Koche R, Staber P, Cusan M . Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia. Cell Stem Cell. 2015; 17(5):611-23. PMC: 4636971. DOI: 10.1016/j.stem.2015.08.011. View

11.

Wang L, Fidler C, Nadig N, Giagounidis A, Della Porta M, Malcovati L . 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. 2008; 93(7):994-1000. DOI: 10.3324/haematol.12603. View

12.

Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M . Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res. 2010; 71(3):955-63. PMC: 3032816. DOI: 10.1158/0008-5472.CAN-10-2933. View

13.

Suragani R, Cadena S, Cawley S, Sako D, Mitchell D, Li R . Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014; 20(4):408-14. DOI: 10.1038/nm.3512. View

14.

Rhyasen G, Wunderlich M, Tohyama K, Garcia-Manero G, Mulloy J, Starczynowski D . An MDS xenograft model utilizing a patient-derived cell line. Leukemia. 2013; 28(5):1142-5. PMC: 4215634. DOI: 10.1038/leu.2013.372. View

15.

Jamieson C, Weissman I, Passegue E . Chronic versus acute myelogenous leukemia: a question of self-renewal. Cancer Cell. 2004; 6(6):531-3. DOI: 10.1016/j.ccr.2004.12.005. View

16.

Garcia-Manero G . Myelodysplastic syndromes: 2015 Update on diagnosis, risk-stratification and management. Am J Hematol. 2015; 90(9):831-41. DOI: 10.1002/ajh.24102. View

17.

Zhou L, Nguyen A, Sohal D, Ma J, Pahanish P, Gundabolu K . Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood. 2008; 112(8):3434-43. PMC: 2569182. DOI: 10.1182/blood-2008-02-139824. View

18.

Kumar M, Narla A, Nonami A, Mullally A, Dimitrova N, Ball B . Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood. 2011; 118(17):4666-73. PMC: 3208282. DOI: 10.1182/blood-2010-12-324715. View

19.

Zhang J, Guo H, Zhang H, Wang H, Qian G, Fan X . Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene Friend leukemia virus integration 1 gene. Cancer. 2010; 117(1):86-95. PMC: 2995010. DOI: 10.1002/cncr.25522. View

20.

Jinnin M, Ihn H, Tamaki K . Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 2005; 69(2):597-607. DOI: 10.1124/mol.105.017483. View