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.

  • Letter to the Editor
  • Published:

Loss of CD44 attenuates aberrant GM-CSF signaling in Kras G12D hematopoietic progenitor/precursor cells and prolongs the survival of diseased animals

Leukemia volume 27, pages 754–757 (2013)Cite this article

Subjects

CD44 is a transmembrane glycoprotein expressed on the surface of many cell types including the majority of myeloid cells and early thymic T-cell progenitors.1 As a cell adhesion molecule, CD44 is differentially required for the adhesion and mobility of different leukemia-initiating cells. In animal models of BCR-ABL-induced human hematopoietic malignancies, CD44 is required for the homing and engraftment of chronic myeloid leukemia-initiating cells, but is dispensable for the engraftment of B-cell lymphoblastic leukemia-initiating cells.2 In contrast, in an animal model of human acute myeloid leukemia, a CD44-activating antibody eradicates leukemia-initiating cells partially by interfering with their interaction with the microenvironment.3 CD44 is also an important regulator of cell signaling and regulates signaling cascades in various ways.1 For example, CD44 can provide specialized platforms for growth factors and matrix metalloproteinases, act as a coreceptor in many receptor complexes and/or organize signaling cascades through association with cytoskeleton.

During tumorigenesis, various signals have been implicated in regulating CD44 expression and/or its alternative splicing. A positive-feedback loop has been identified to couple the activation of Ras/ERK signaling and induction of CD44 expression, in particular expression of its splicing variant v6.4 Ras signaling promotes CD44v6 expression, and in turn CD44v6 sustains late Ras signaling. Consistent with this finding, we and others previously reported that CD44 is invariably overexpressed in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by endogenous oncogenic Kras (Kras G12D) or oncogenic Nras.5, 6, 7

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

References

  1. Ponta H, Sherman L, Herrlich PA . CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003; 4: 33–45.

    Article  CAS  PubMed  Google Scholar 

  2. Krause DS, Lazarides K, von Andrian UH, Van Etten RA . Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med 2006; 12: 1175–1180.

    Article  CAS  PubMed  Google Scholar 

  3. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167–1174.

    Article  PubMed  Google Scholar 

  4. Cheng C, Yaffe MB, Sharp PA . A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev 2006; 20: 1715–1720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kindler T, Cornejo MG, Scholl C, Liu J, Leeman DS, Haydu JE et al. K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. Blood 2008; 112: 3373–3382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang J, Wang J, Liu Y, Sidik H, Young KH, Lodish HF et al. Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation. Blood 2009; 113: 1304–1314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang JY, Liu YG, Li ZY, Wang ZD, Tan LX, Ryu MJ et al. Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner. Blood 2011; 118: 368–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cavalcanti Junior GB, Savino W . Pombo-de-Oliveira MS. CD44 expression in T-cell lymphoblastic leukemia. Braz J Med Biol Res 1994; 27: 2259–2266.

    CAS  PubMed  Google Scholar 

  9. Chen C, Chang MC, Hsieh RK, Chang YF, Lin J, Tsan KW . Activation of CD44 facilitates DNA repair in T-cell lymphoma but has differential effects on apoptosis induced by chemotherapeutic agents and ionizing radiation. Leuk Lymphoma 2005; 46: 1785–1795.

    Article  CAS  PubMed  Google Scholar 

  10. Protin U, Schweighoffer T, Jochum W, Hilberg F . CD44-deficient mice develop normally with changes in subpopulations and recirculation of lymphocyte subsets. J Immunol 1999; 163: 4917–4923.

    CAS  PubMed  Google Scholar 

  11. Wang JY, Liu YG, Li ZY, Du J, Ryu MJ, Taylor PR et al. Endogenous oncogenic Nras mutation leads to aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood 2010; 116: 5991–6002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sabnis AJ, Cheung LS, Dail M, Kang HC, Santaguida M, Hermiston ML et al. Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol 2009; 7: e59.

    Article  PubMed  Google Scholar 

  13. Ashworth TD, Pear WS, Chiang MY, Blacklow SC, Mastio J, Xu L et al. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 2010; 116: 5455–5464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shi M, Dennis K, Peschon JJ, Chandrasekaran R, Mikecz K . Antibody-induced shedding of CD44 from adherent cells is linked to the assembly of the cytoskeleton. J Immunol 2001; 167: 123–131.

    Article  CAS  PubMed  Google Scholar 

  15. Zheng Z, Katoh S, He Q, Oritani K, Miyake K, Lesley J et al. Monoclonal antibodies to CD44 and their influence on hyaluronan recognition. J Cell Biol 1995; 130: 485–495.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs David A Tuveson and Tyler E Jacks for generously providing us with conditional oncogenic Kras mice and Bruce Bagley for helping us detect Type 2 deletion in Notch1. We are grateful to Drs Qiang Chang, Norman Drinkwater and Shannon Kenney for helpful discussion and critical comments on the paper. We thank the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work was supported by a Howard Temin Award and a R01 grant 1R01CA152108 from the National Cancer Institute, a Shaw Scientist Award from the Greater Milwaukee Foundation, an ASH Scholar Award from the American Society of Hematology, a V Scholar Award from the V Foundation for Cancer Research, and an Investigator Initiated Grant from UWCCC to Jing Zhang. This work was also supported in part by NIH/NCI P30 CA014520--UW Comprehensive Cancer Center Support.

Author contributions

The contributions of individual authors are listed below: Juan Du for experimental design and execution, as well as writing the paper; Yangang Liu, Benjamin Meline, Guangyao Kong, Li Xuan Tan, Juinn Cherng Lo, Jinyong Wang, Li Zhang, Yuan-I Chang, Myung-Jeom Ryu and Jingfang Zhang for experimental execution; Erik A Ranheim for histopathology analysis; Jing Zhang for experimental design and writing the paper.

Author information

Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA

    J Du, Y Liu, G Kong, J Wang, L Zhang, Y I Chang, M J Ryu, J F Zhang & J Zhang

  2. Department of Molecular and Cellular Pharmacology, University of Wisconsin-Madison, Madison, WI, USA

    B Meline

  3. Department of Genetics, University of Wisconsin-Madison, Madison, WI, USA

    L X Tan & J C Lo

  4. Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    E Ranheim

Authors
  1. J Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Meline
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L X Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J C Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Ranheim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y I Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M J Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J F Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Zhang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Du, J., Liu, Y., Meline, B. et al. Loss of CD44 attenuates aberrant GM-CSF signaling in Kras G12D hematopoietic progenitor/precursor cells and prolongs the survival of diseased animals. Leukemia 27, 754–757 (2013). https://doi.org/10.1038/leu.2012.251

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.251

This article is cited by

Search

Advanced search

Quick links