Prognostic Significance of CD44v6/v7 in Acute Promyelocytic Leukemia

  • Chen, Ping (Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology) ;
  • Huang, Hui-Fang (Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology) ;
  • Lu, Rong (Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology) ;
  • Wu, Yong (Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology) ;
  • Chen, Yuan-Zhong (Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology)
  • Published : 2012.08.31


CD44v, especially splice variants containing exon v6, has been shown to be related closely to development of different tumors. High levels of CD44v6/v7 have been reported to be associated with invasiveness and metastasis of many malignancies. The objective of this study was to detect expression of CD44v6-containing variants in patients with acute promyelocytic leukemia (APL) and evaluate the potential of CD44v6/v7 for risk stratification. Reverse transcription polymerase chain reaction (RT-PCR) followed by PCR product purification, ligation into T vectors and positive clone sequencing were used to detect CD44 v6-containing variant isoforms in 23 APL patients. Real-time quantitative PCR of the CD44v6/v7 gene was performed in patients with APL and in NB4 cells that were treated with all-trans retinoic acid (ATRA) or arsenic trioxide ($As_2O_3$). Sequencing results identified four isoforms (CD44v6/v7, CD44v6/v8/v10, CD44v6/v8/v9/v10, and CD44v6/v7/v8/v9/v10) in bone marrow mononuclear cells of 23 patients with APL. The level of CD44v6/v7 in high-risk cases was significantly higher than those with low-risk. Higher levels of CD44v6/v7 were found in three patients with central nervous system relapse than in other patients inthe same risk group. Furthermore, in contrast to ATRA, only $As_2O_3$ could significantly down-regulate CD44v6/v7 expression in NB4 cells. Our data suggest that CD44v6/v7 expression may be a prognostic indicator for APL.


  1. Akisik E, Bavbek S, Dalay N (2002). CD44 variant exons in leukemia and lymphoma. Pathology Oncology Research, 8, 36-40.
  2. Bendall LJ, Bradstock KF, Gottlieb DJ (2000). Expression of CD44 variant exons in acute myeloid leukemia is more common and more complex than that observed in normal blood, bone marrow or CD341 cells. Leukemia, 14, 1239-46.
  3. Brown D, Kogan S, Lagasse E, et al (1994). A PML RARalpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci U S A, 94, 2551-6.
  4. Chakraborty G, Jan S, Behera R, et al (2006). The multifaceted roles of osteopontin in cell signaling, tumor progression and angiogenesis.Curr Mol Med, 6, 819-30.
  5. Chun SY, Bae OS, Kim JB (2000). The significance of CD44 variants expression in colorectal cancer and its regional lymph nodes. J Korean Med Sci, 6, 696-700.
  6. Colovic N, Bogdanovic A, Miljic P, Jankovic G, Colovic M (2002). Central nervous system relapse in acute promyelocytic leukemia. Am J Hematol, 71, 60-1.
  7. Cristiana B, Carla O, Xiaogang W, et al (2010). De novo expression of CD44 variants in sporadic and hereditary gastric cancer. Lab Invest, 90, 1604-14.
  8. Fenaux P, Chevret S, Guerci A, et al (2000). Long-term followup confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia, 14, 1371-7.
  9. Herold Mende C, Seiter S, Born AI, et al (1996). Expression of CD44 splice variants in squamous epithelia and squamous cell carcinomas of the head and neck. J Pathol, 179, 662-731.
  10. Hu J, Shen ZX, Sun G, et al (1999). Long-term survival and prognostic study in acute promyelocytic leukemia treated with all-trans-retinoic acid, chemotherapy, and $As_{2}O_{3}$: an experience of 120 patients at a single institution. Int J Hematol, 70, 248-60.
  11. Katarigi YU, Sleeman J, Fujii H, et al (1999). CD44 Variants but not CD44s cooperate with b1-containing integrins to permit cells to bind to osteopontin independently of arginineglycine- aspartic acid, thereby stimulatingcell motility and chemotaxis. Cancer Research, 59, 219-26.
  12. Kortlepel K, Bendall LJ, Gottlieb DJ (1993). Human acute myeloid leukemia cells express adhesion proteins and bind to bone marrow fibroblast monolayers and extracellular matrix proteins. Leukemia, 7, 1174-9.
  13. Marroquin CE, Downey L, Guo H, Kuo PC (2004). Osteopontin increases CD44 expression and cell adhesion in RAW 264.7 murine leukemia cells. Immunology Letters, 15, 109-12.
  14. Naor D, Wallach-Dayan SB, Zahalka MA, Sionov RV (2008). Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Seminars in Cancer Biology, 18, 260-7.
  15. Pamela K, Rachid M, Thorsten J, et al (2009). CD44 variant isoforms promote metastasis formation by a tumor cellmatrix cross-talk that supports adhesion and apoptosis resistance. Molecular Cancer Research, 7, 168-79.
  16. Ponta H, Sherman L, Herrlich PA (2003). CD44: from adhesion molecules to signaling regulators. Nature Reviews Molecular Cell Biology, 4, 33-45.
  17. Powell JA, Thomas D, Barry EF, et al (2009). Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML. Blood, 114, 4859-70.
  18. Sanz MA, Lo Coco F, Martin G, et al (2000). Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA copperative groups. Blood, 96, 1247-53.
  19. Tallman MS, Andersen JW, Schiffer CA, et al (2002). All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood, 100, 4298-302.
  20. Wolfgang R, Martin H, Reinhard SA, et al (1993). The two major CD44 proteins expressed on a metastatic rat tumor cell line are derived from different splice variants: each one individually suffices to confer metastatic behavior. Cancer Research, 53, 1262-8.
  21. Yu P,Zhou L, Ke W, et al(2010). Clinical significance of pAKT and CD44v6 overexpression with breast cancer. J Cancer Res Clin Oncol, 136:1283-92
  22. Zhang AM, Fan Y, Yao Q, et al (2012). Identification of a cancer stem-like population in the Lewis lung cancer cell line. Asian Pac J Cancer Prev, 13, 761-6.
  23. Zhang LS, Ma HW, Greyner HJ, et al (2010). Inhibition of cell proliferation by CD44: Akt is inactivated and EGR-1 is down-regulated. Cell Prolif, 43, 385-95.
  24. Zhang XW, Yan XJ, Zhou ZR, et al (2010). Arsenic trioxide controls the fate of the PML-RARa oncoprotein by directly binding PML. Science, 328, 240-3.
  25. Zheng X, Seshire A, Ruster B, et al (2007). Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RARalpha-positive leukemic stem cells. Haematologica, 92, 323-31.

Cited by

  1. Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis vol.15, pp.16, 2014,
  2. Acute Promyelocytic Leukemia: a Single Center Study from Southern Pakistan vol.16, pp.17, 2015,