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Annals of Hematology

, Volume 90, Issue 8, pp 901–909 | Cite as

In situ RHAMM protein expression in acute myeloid leukemia blasts suggests poor overall survival

  • Alexandar Tzankov
  • Ulrich Strasser
  • Stephan Dirnhofer
  • Thomas Menter
  • Caroline Arber
  • Martine Jotterand
  • Alicia Rovo
  • Andre Tichelli
  • Reinhard Stauder
  • Ursula Günthert
Original Article

Abstract

Treatment options for patients with high-risk acute myeloid leukemia (AML) include high-dose chemotherapy regimens in combination with allogeneic hematopoietic stem cell transplantation, which takes advantage of the donor T-cell-mediated graft-versus-leukemia effect. Together with beneficial responses observed in assays targeted at leukemia-associated antigens (LAA), this encouraged research on cancer vaccines and adoptive cellular therapies in AML. The receptor for hyaluronic acid-mediated motility (RHAMM, CD168) was identified as one of the most promising LAA in AML. Thus far, little is known about in situ expression in leukemic bone marrow blasts or the prognostic role of RHAMM and its interaction partners in AML. We immunohistochemically analyzed the expression and prognostic significance of RHAMM on trephine bone marrow biopsies from 71 AML cases that had been evaluated for cytogenetics and presence of FLT3-internal tandem duplications and NPM1 mutations. Fifty-five patients (77%) were treated with curative intent, while 16 (23%) received the most appropriate supportive care. Twenty of 71 (28%) AML cases were considered RHAMM+. Receiver operating characteristic curves showed significant discriminatory power considering overall survival (OS) in AML patients treated curatively for RHAMM (p = 0.015). Multivariable analysis revealed that expression of RHAMM in >5% of leukemic blasts identifies a subgroup of curatively treated cases with adverse OS independent of failures to achieve complete remission. RHAMM not only represents a promising LAA with specific T-cell responses in AML but, if assessed in situ on blasts, also a probable prognostic factor.

Keywords

AML RHAMM CD44 Prognosis 

Notes

Acknowledgment

The study was supported by the Oncosuisse grant OCS-01792-10-2005.

References

  1. 1.
    Estey E, Dohner H (2006) Acute myeloid leukaemia. Lancet 368:1894–1907PubMedCrossRefGoogle Scholar
  2. 2.
    Löwenberg B (2008) Diagnosis and prognosis in acute myeloid leukemia—the art of distinction. N Engl J Med 358:1960–1962PubMedCrossRefGoogle Scholar
  3. 3.
    Santamaria CM, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Ramos F et al (2009) Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia. Blood 114:148–152PubMedCrossRefGoogle Scholar
  4. 4.
    Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, Thiele J, Vardiman J (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, LyonGoogle Scholar
  5. 5.
    Wahlin A, Billstrom R, Bjor O, Ahlgren T, Hedenus M, Hoglund M et al (2009) Results of risk-adapted therapy in acute myeloid leukaemia. A long-term population-based follow-up study. Eur J Haematol 83:99–107PubMedCrossRefGoogle Scholar
  6. 6.
    Greiner J, Bullinger L, Guinn BA, Dohner H, Schmitt M (2008) Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells. Clin Cancer Res 14:7161–7166PubMedCrossRefGoogle Scholar
  7. 7.
    Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A et al (2006) Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches. Blood 108:4109–4117PubMedCrossRefGoogle Scholar
  8. 8.
    Li L, Reinhardt P, Schmitt A, Barth TF, Greiner J, Ringhoffer M et al (2005) Dendritic cells generated from acute myeloid leukemia (AML) blasts maintain the expression of immunogenic leukemia associated antigens. Cancer Immunol Immunother 54:685–693PubMedCrossRefGoogle Scholar
  9. 9.
    Giannopoulos K, Li L, Bojarska-Junak A, Rolinski J, Dmoszynska A, Hus I et al (2006) Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia. Int J Oncol 29:95–103PubMedGoogle Scholar
  10. 10.
    Giannopoulos K, Mertens D, Buhler A, Barth TF, Idler I, Moller P et al (2009) The candidate immunotherapeutical target, the receptor for hyaluronic acid-mediated motility, is associated with proliferation and shows prognostic value in B-cell chronic lymphocytic leukemia. Leukemia 23:519–527PubMedCrossRefGoogle Scholar
  11. 11.
    Greiner J, Ringhoffer M, Taniguchi M, Hauser T, Schmitt A, Dohner H, Schmitt M (2003) Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. Int J Cancer 106:224–231PubMedCrossRefGoogle Scholar
  12. 12.
    Greiner J, Ringhoffer M, Taniguchi M, Li L, Schmitt A, Shiku H, Dohner H, Schmitt M (2004) mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int J Cancer 108:704–711PubMedCrossRefGoogle Scholar
  13. 13.
    Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krahn G et al (2002) Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Exp Hematol 30:1029–1035PubMedCrossRefGoogle Scholar
  14. 14.
    Sherman L, Sleeman J, Herrlich P, Ponta H (1994) Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. Curr Opin Cell Biol 6:726–733PubMedCrossRefGoogle Scholar
  15. 15.
    Tölg C, Hamilton SR, Nakrieko KA, Kooshesh F, Walton P, McCarthy JB, Bissell MJ, Turley EA (2006) Rhamm-/- fibroblasts are defective in CD44-mediated ERK1, 2 motogenic signaling, leading to defective skin wound repair. J Cell Biol 175:1017–1028PubMedCrossRefGoogle Scholar
  16. 16.
    Turley EA, Belch AJ, Poppema S, Pilarski LM (1993) Expression and function of a receptor for hyaluronan-mediated motility on normal and malignant B lymphocytes. Blood 81:446–453PubMedGoogle Scholar
  17. 17.
    Wang C, Thor AD, Moore DH 2nd, Zhao Y, Kerschmann R, Stern R, Watson PH, Turley EA (1998) The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Clin Cancer Res 4:567–576PubMedGoogle Scholar
  18. 18.
    Hamilton SR, Fard SF, Paiwand FF, Tölg C, Veiseh M, Wang C et al (2007) The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1, 2 that sustain high basal motility in breast cancer cells. J Biol Chem 282:16667–16680PubMedCrossRefGoogle Scholar
  19. 19.
    Maxwell CA, McCarthy J, Turley E (2008) Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci 121:925–932PubMedCrossRefGoogle Scholar
  20. 20.
    Bourguignon LY, Gunja-Smith Z, Iida N, Zhu HB, Young LJ, Muller WJ, Cardiff RD (1998) CD44v(3, 8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells. J Cell Physiol 176:206–215PubMedCrossRefGoogle Scholar
  21. 21.
    Godar S, Weinberg RA (2008) Filling the mosaic of p53 actions: p53 represses RHAMM expression. Cell Cycle 7:3479PubMedCrossRefGoogle Scholar
  22. 22.
    Khan SA, Cook AC, Kappil M, Günthert U, Chambers AF, Tuck AB, Denhardt DT (2005) Enhanced cell surface CD44 variant (v6, v9) expression by osteopontin in breast cancer epithelial cells facilitates tumor cell migration: novel post-transcriptional, post-translational regulation. Clin Exp Metastasis 22:663–673PubMedCrossRefGoogle Scholar
  23. 23.
    Tzircotis G, Thorne RF, Isacke CM (2005) Chemotaxis towards hyaluronan is dependent on CD44 expression and modulated by cell type variation in CD44-hyaluronan binding. J Cell Sci 118:5119–5128PubMedCrossRefGoogle Scholar
  24. 24.
    Sohr S, Engeland K (2008) RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle 7:3448–3460PubMedCrossRefGoogle Scholar
  25. 25.
    Schmitt A, Barth TF, Beyer E, Borchert F, Rojewski M, Chen J et al (2009) The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses. Int J Oncol 34:629–639PubMedCrossRefGoogle Scholar
  26. 26.
    Gust KM, Hofer MD, Perner SR, Kim R, Chinnaiyan AM, Varambally S et al (2009) RHAMM (CD168) is overexpressed at the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease. Neoplasia 11:956–963PubMedGoogle Scholar
  27. 27.
    Maxwell CA, Rasmussen E, Zhan F, Keats JJ, Adamia S, Strachan E et al (2004) RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma. Blood 104:1151–1158PubMedCrossRefGoogle Scholar
  28. 28.
    Nagel S, Hirschmann P, Dirnhofer S, Günthert U, Tzankov A (2010) Coexpression of CD44 variant isoforms and receptor for hyaluronic acid-mediated motility (RHAMM, CD168) is an International Prognostic Index and C-MYC gene status-independent predictor of poor outcome in diffuse large B-cell lymphomas. Exp Hematol 38:38–45PubMedCrossRefGoogle Scholar
  29. 29.
    Pilarski LM, Masellis-Smith A, Belch AR, Yang B, Savani RC, Turley EA (1994) RHAMM, a receptor for hyaluronan-mediated motility, on normal human lymphocytes, thymocytes and malignant B cells: a mediator in B cell malignancy? Leuk Lymphoma 14:363–374PubMedCrossRefGoogle Scholar
  30. 30.
    Rein DT, Roehrig K, Schondorf T, Lazar A, Fleisch M, Niederacher D, Bender HG, Dall P (2003) Expression of the hyaluronan receptor RHAMM in endometrial carcinomas suggests a role in tumour progression and metastasis. J Cancer Res Clin Oncol 129:161–164PubMedGoogle Scholar
  31. 31.
    Shigeishi H, Fujimoto S, Hiraoka M, Ono S, Taki M, Ohta K, Higashikawa K, Kamata N (2009) Overexpression of the receptor for hyaluronan-mediated motility, correlates with expression of microtubule-associated protein in human oral squamous cell carcinomas. Int J Oncol 34:1565–1571PubMedCrossRefGoogle Scholar
  32. 32.
    Zlobec I, Terracciano L, Tornillo L, Günthert U, Vuong T, Jass JR, Lugli A (2008) Role of RHAMM within the hierarchy of well-established prognostic factors in colorectal cancer. Gut 57:1413–1419PubMedCrossRefGoogle Scholar
  33. 33.
    Mielgo A, van Driel M, Bloem A, Landmann L, Günthert U (2006) A novel antiapoptotic mechanism based on interference of Fas signaling by CD44 variant isoforms. Cell Death Differ 13:465–477PubMedCrossRefGoogle Scholar
  34. 34.
    Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45PubMedCrossRefGoogle Scholar
  35. 35.
    Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12:1167–1174PubMedCrossRefGoogle Scholar
  36. 36.
    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al (2003) Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642–4649PubMedCrossRefGoogle Scholar
  37. 37.
    Schreck RR, Distèche CM (2001) Chromosome banding techniques. In: Haines JL, Korf BR, Morton CC, Seidman EG, Seidman JG, Smith DR, Sharer JD (eds) Current protocols in human genetics. Wiley, New York, pp 4.2.1–4.2.36Google Scholar
  38. 38.
    Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ et al (2001) The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98:1312–1320PubMedCrossRefGoogle Scholar
  39. 39.
    Obermann EC, Arber C, Jotterand M, Tichelli A, Hirschmann P, Tzankov A (2010) Expression of pSTAT5 predicts FLT3 internal tandem duplications in acute myeloid leukemia. Ann Hematol 89:663–669PubMedCrossRefGoogle Scholar
  40. 40.
    Atkins D, Reiffen KA, Tegtmeier CL, Winther H, Bonato MS, Storkel S (2004) Immunohistochemical detection of EGFR in paraffin-embedded tumor tissues: variation in staining intensity due to choice of fixative and storage time of tissue sections. J Histochem Cytochem 52:893–901PubMedCrossRefGoogle Scholar
  41. 41.
    Zlobec I, Terracciano L, Jass JR, Lugli A (2007) Value of staining intensity in the interpretation of immunohistochemistry for tumor markers in colorectal cancer. Virchows Arch 451:763–769PubMedCrossRefGoogle Scholar
  42. 42.
    Tzankov A, Zlobec I, Went P, Robl H, Hoeller S, Dirnhofer S (2010) Prognostic immunophenotypic biomarker studies in diffuse large B cell lymphoma with special emphasis on rational determination of cut-off scores. Leuk Lymphoma 51:199–212PubMedCrossRefGoogle Scholar
  43. 43.
    Chen K, Liu J, Heck S, Chasis JA, An X, Mohandas N (2009) Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci U S A 106:17413–17418PubMedCrossRefGoogle Scholar
  44. 44.
    Pilarski LM, Pruski E, Wizniak J, Paine D, Seeberger K, Mant MJ, Brown CB, Belch AR (1999) Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells. Blood 93:2918–2927PubMedGoogle Scholar
  45. 45.
    Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E, Hoelzer D (1997) High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 90:1217–1225PubMedGoogle Scholar
  46. 46.
    Yanada M, Terakura S, Yokozawa T, Yamamoto K, Kiyoi H, Emi N et al (2004) Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia. Leuk Lymphoma 45:1803–1808PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Alexandar Tzankov
    • 1
  • Ulrich Strasser
    • 1
    • 2
  • Stephan Dirnhofer
    • 1
  • Thomas Menter
    • 1
  • Caroline Arber
    • 3
  • Martine Jotterand
    • 4
  • Alicia Rovo
    • 3
  • Andre Tichelli
    • 3
  • Reinhard Stauder
    • 5
  • Ursula Günthert
    • 1
  1. 1.Institute of PathologyUniversity Hospital BaselBaselSwitzerland
  2. 2.Institute of PathologyMedical University of InnsbruckInnsbruckAustria
  3. 3.HematologyUniversity Hospital BaselBaselSwitzerland
  4. 4.Service de génétique médicaleCHUVLausanneSwitzerland
  5. 5.Department of Internal Medicine V (Hematology and Oncology)Medical University of InnsbruckInnsbruckAustria

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