[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute myeloid leukemia

Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis

Leukemia volume 34, pages 1027–1037 (2020)Cite this article

Subjects

Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is propagated by leukemic stem cells (LSCs), often characterized by deregulated Wnt signaling. We previously showed that the central transcriptional mediator of Wnt signaling LEF1 is able to cause AML in mice and acts as an independent prognostic factor in normal karyotype AML. Here, we show that treatment naïve normal karyotype AML as well as samples AML LSCs predominantly express the long β-catenin-binding isoform of LEF1 in sharp contrast to normal human hematopoietic stem cells, which lack expression of the long isoform, but express the short N-terminally truncated isoform with loss of the β-catenin-binding site. Gene expression and ChiP-Seq analyses in mice linked the long isoform to Wnt-β-catenin signaling and oncogenic pathways, the N-terminally truncated isoform to stemness associated genes. Approaches impairing binding of LEF1 to β-catenin significantly impaired AML growth, but spared normal hematopoietic stem cells. This report now demonstrates a striking difference of LEF1 isoform expression between normal and AML cells, contributing to higher vulnerability of leukemic cells to approaches targeting β-catenin/LEF1 interaction.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17:1086–93.

    Article  CAS  PubMed  Google Scholar 

  3. Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.

    Article  CAS  PubMed  Google Scholar 

  4. Pollyea DA, Jordan CT. Therapeutic targeting of acute myeloid leukemia stem cells. Blood. 2017;129:1627–35.

    Article  CAS  PubMed  Google Scholar 

  5. Pei S, Minhajuddin M, Adane B, Khan N, Stevens BM, Mack SC, et al. AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells. Cell Stem Cell. 2018;23:86–100 e106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.

    Article  CAS  PubMed  Google Scholar 

  7. Simon M, Grandage VL, Linch DC, Khwaja A. Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia. Oncogene. 2005;24:2410–20.

    Article  CAS  PubMed  Google Scholar 

  8. Eaves CJ, Humphries RK. Acute myeloid leukemia and the Wnt pathway. N Engl J Med. 2010;362:2326–7.

    Article  CAS  PubMed  Google Scholar 

  9. Reya T, O’Riordan M, Okamura R, Devaney E, Willert K, Nusse R, et al. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity. 2000;13:15–24.

    Article  CAS  PubMed  Google Scholar 

  10. Travis A, Amsterdam A, Belanger C, Grosschedl R. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev. 1991;5:880–94.

    Article  CAS  PubMed  Google Scholar 

  11. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA. 1999;96:5522–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Skokowa J, Cario G, Uenalan M, Schambach A, Germeshausen M, Battmer K, et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med. 2006;12:1191–7.

    Article  CAS  PubMed  Google Scholar 

  13. Skokowa J, Klimiankou M, Klimenkova O, Lan D, Gupta K, Hussein K, et al. Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat Med. 2012;18:1550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657–67.

    Article  CAS  PubMed  Google Scholar 

  15. Hovanes K, Li TW, Munguia JE, Truong T, Milovanovic T, Lawrence Marsh J, et al. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet. 2001;28:53–57.

    CAS  PubMed  Google Scholar 

  16. Li TW, Ting JH, Yokoyama NN, Bernstein A, van de Wetering M, Waterman ML. Wnt activation and alternative promoter repression of LEF1 in colon cancer. Mol Cell Biol. 2006;26:5284–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yokoyama NN, Pate KT, Sprowl S, Waterman ML. A role for YY1 in repression of dominant negative LEF-1 expression in colon cancer. Nucleic Acids Res. 2010;38:6375–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Petropoulos K, Arseni N, Schessl C, Stadler CR, Rawat VP, Deshpande AJ, et al. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med. 2008;205:515–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Edmaier KE, Stahnke K, Vegi N, Mulaw M, Ihme S, Scheffold A, et al. Expression of the lymphoid enhancer factor 1 is required for normal hematopoietic stem and progenitor cell function. Leukemia. 2014;28:227–30.

    Article  CAS  PubMed  Google Scholar 

  20. Metzeler KH, Heilmeier B, Edmaier KE, Rawat VP, Dufour A, Dohner K, et al. High expression of lymphoid enhancer-binding factor-1 (LEF1) is a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia. Blood. 2012;120:2118–26.

    Article  CAS  PubMed  Google Scholar 

  21. Anjos-Afonso F, Currie E, Palmer HG, Foster KE, Taussig DC, Bonnet D. CD34(-) cells at the apex of the human hematopoietic stem cell hierarchy have distinctive cellular and molecular signatures. Cell Stem Cell. 2013;13:161–74.

    Article  CAS  PubMed  Google Scholar 

  22. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333:218–21.

    Article  CAS  PubMed  Google Scholar 

  23. Hsieh TH, Hsu CY, Tsai CF, Chiu CC, Liang SS, Wang TN, et al. A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting beta-catenin/LEF-1 signaling. Sci Rep. 2016;6:19156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gandhirajan RK, Staib PA, Minke K, Gehrke I, Plickert G, Schlosser A, et al. Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Neoplasia. 2010;12:326–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004;5:91–102.

    Article  CAS  PubMed  Google Scholar 

  26. Minke KS, Staib P, Puetter A, Gehrke I, Gandhirajan RK, Schlosser A, et al. Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells. Eur J Haematol. 2009;82:165–75.

    Article  CAS  PubMed  Google Scholar 

  27. Nakamura T, Nakamura T, Matsumoto K. The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology. J Cell Mol Med. 2008;12:391–408.

    Article  CAS  PubMed  Google Scholar 

  28. Fuchs SY, Chen A, Xiong Y, Pan ZQ, Ronai ZHOS. a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. Oncogene. 1999;18:2039–46.

    Article  CAS  PubMed  Google Scholar 

  29. Stein SJ, Baldwin AS. Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. Blood. 2013;121:5015–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Staal FJ, Famili F, Garcia Perez L, Pike-Overzet K. Aberrant Wnt signaling in leukemia. Cancers Basel. 2016;8:1–15.

  31. Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D, et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer cell. 2010;18:606–18.

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327:1650–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Valencia A, Roman-Gomez J, Cervera J, Such E, Barragan E, Bolufer P, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23:1658–66.

    Article  CAS  PubMed  Google Scholar 

  34. Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A, et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell. 2003;4:349–60.

    Article  CAS  PubMed  Google Scholar 

  35. Famili F, Brugman MH, Taskesen E, Naber BEA, Fodde R, Staal FJT. High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells. Stem Cell Rep. 2016;6:652–9.

    Article  CAS  Google Scholar 

  36. Famili F, Naber BA, Vloemans S, de Haas EF, Tiemessen MM, Staal FJ. Discrete roles of canonical and non-canonical Wnt signaling in hematopoiesis and lymphopoiesis. Cell Death Dis. 2015;6:e1981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sugimura R, He XC, Venkatraman A, Arai F, Box A, Semerad C, et al. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell. 2012;150:351–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vacik T, Lemke G. Dominant-negative isoforms of Tcf/Lef proteins in development and disease. Cell Cycle. 2011;10:4199–4200.

    Article  CAS  PubMed  Google Scholar 

  39. Mikels AJ, Nusse R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol. 2006;4:e115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakamura T, Aoki S, Kitajima K, Takahashi T, Matsumoto K, Nakamura T. Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein. Biochim Biophys Acta. 2001;1518:63–72.

    Article  CAS  PubMed  Google Scholar 

  41. Zebisch M, Jackson VA, Zhao Y, Jones EY. Structure of the dual-mode Wnt regulator Kremen1 and insight into ternary complex formation with LRP6 and Dickkopf. Structure. 2016;24:1599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bungartz G, Land H, Scadden DT, Emerson SG. NF-Y is necessary for hematopoietic stem cell proliferation and survival. Blood. 2012;119:1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dolfini D, Minuzzo M, Pavesi G, Mantovani R. The short isoform of NF-YA belongs to the embryonic stem cell transcription factor circuitry. Stem Cells. 2012;30:2450–9.

    Article  CAS  PubMed  Google Scholar 

  44. Gonzalez-Sancho JM, Aguilera O, Garcia JM, Pendas-Franco N, Pena C, Cal S, et al. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene. 2005;24:1098–103.

    Article  CAS  PubMed  Google Scholar 

  45. Zimmerli D, Hausmann G, Cantu C, Basler K. Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors. Br J Pharm. 2017;174:4600–10.

    Article  CAS  Google Scholar 

  46. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Disco. 2014;13:513–32.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all members of the Core Facility FACS, Core Facility Genomics of the University Ulm and the animal facility of the Helmholtz Centre Munich and the University Ulm for breeding and maintenance of the animals. The work was supported by the grant from the DFG (SFB 1074 project A4 to KF and CB, A6 to MFB, Z1 to CB, HAK and JMK and B3 to KD) and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – GRK 1789.

Author information

Author notes

  1. These author contributed equally Kristin Feder, Katrin Edmaier-Schröger

Authors and Affiliations

  1. Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081, Ulm, Germany

    Kristin Feder, Katrin Edmaier-Schröger, Vijay P. S. Rawat, Nicole Kirsten, Michaela Feuring-Buske & Christian Buske

  2. Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany

    Klaus Metzeler

  3. Institute of Medical Systems Biology, Ulm University, 89081, Ulm, Germany

    Johann M. Kraus & Hans A. Kestler

  4. Department of Internal Medicine III, University Hospital Ulm, 89081, Ulm, Germany

    Konstanze Döhner, Hartmut Döhner & Michaela Feuring-Buske

Authors
  1. Kristin Feder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrin Edmaier-Schröger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vijay P. S. Rawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicole Kirsten
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klaus Metzeler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johann M. Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Konstanze Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hartmut Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hans A. Kestler
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michaela Feuring-Buske
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christian Buske
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Buske.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feder, K., Edmaier-Schröger, K., Rawat, V.P.S. et al. Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis. Leukemia 34, 1027–1037 (2020). https://doi.org/10.1038/s41375-019-0635-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0635-1

Search

Advanced search

Quick links