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.

  • Original Manuscript
  • Published:

Clinical Laboratory Correlates and Prognosis in AML

High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML)

Leukemia volume 16, pages 22–29 (2002)Cite this article

Abstract

The search for molecular markers in AML that allow prediction of outcome has recently focused on genes involved in the regulation of programmed cell death (PCD). The aim of our study was to determine whether mRNA levels of Mdm-2, Bcl-2, Bcl-xL, Bad, and Bax are independent prognostic parameters for outcome. Transcript levels were analyzed by real-time quantitative RT-PCR in 232 samples collected either at diagnosis or following induction chemotherapy (ICT). Multivariate COX regression analysis adjusted for chemotherapy protocol, de novo vs secondary AML, and de novo vsrelapsed AML indicated: (1) At diagnosis, high expression of Bad (P = 0.015) and even more so high Bax and Bad levels (P = 0.018) predicted adverse outcome, regardless of the response to ICT. In patients who subsequently failed to enter complete remission (CR), high levels of Bad, Bax and Bax high/Bad high were associated with an increased relative risk (RR) to die from tumor (RR = 5.0 for Bad, 3.4 for Bax and 6.14 for Bax high/Bad high). (2) Following ICT, high expression of Bax (P = 0.005) and high Bcl-2/Bax ratios (P = 0.004) were independent predictors of unfavorable outcome, regardless of response to ICT. We conclude that high levels of Bax and Bad correlate with poor outcome, particularly in patients who do not enter CR and may serve as prognostic markers in AML.

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

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

Similar content being viewed by others

References

  1. Licht T, Pastan I, Gottesman MM, Herrmann F . The multidrug-resistance gene in gene therapy of cancer and hematopoietic disorders Ann Hematol 1996 72: 184–193

    Article  CAS  Google Scholar 

  2. McKenna SL, Padua RA . Multidrug resistance in leukaemia Br J Haematol 1997 96: 659–674

    Article  CAS  Google Scholar 

  3. Bargou RC, Wagener C, Bommert K, Mapara MY, Daniel PT, Arnold W, Dietel M, Guski H, Feller A, Royer HD, Dorken B . Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice J Clin Invest 1996 97: 2651–2659

    Article  CAS  Google Scholar 

  4. Friess H, Lu Z, Graber HU, Zimmermann A, Adler G, Korc M, Schmid RM, Buchler MW . bax, but not bcl-2, influences the prognosis of human pancreatic cancer Gut 1998 43: 414–421

    Article  CAS  Google Scholar 

  5. Feinmesser M, Halpern M, Fenig E, Tsabari C, Hodak E, Sulkes J, Brenner B, Okon E . Expression of the apoptosis-related oncogenes bcl-2, bax, and p53 in Merkel cell carcinoma: can they predict treatment response and clinical outcome? Hum Pathol 1999 30: 1367–1372

    Article  CAS  Google Scholar 

  6. Sturm I, Kohne CH, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dorken B, Daniel PT . Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases J Clin Oncol 1999 17: 1364–1374

    Article  CAS  Google Scholar 

  7. Apolinario RM, van der Valk P, de Jong JS, Deville W, van Ark-Otte J, Dingemans AM, van Mourik JC, Postmus PE, Pinedo HM, Giaccone G . Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small- cell lung cancer J Clin Oncol 1997 15: 2456–2466

    Article  CAS  Google Scholar 

  8. Marx D, Binder C, Meden H, Lenthe T, Ziemek T, Hiddemann T, Kuhn W, Schauer A . Differential expression of apoptosis associated genes bax and bcl-2 in ovarian cancer Anticancer Res 1997 17: 2233–2240

    CAS  PubMed  Google Scholar 

  9. Hogarth LA, Hall AG . Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia Blood 1999 93: 2671–2678

    CAS  PubMed  Google Scholar 

  10. Deng G, Lane C, Kornblau S, Goodacre A, Snell V, Andreeff M, Deisseroth AB . Ratio of bcl-xshort to bcl-xlong is different in good- and poor-prognosis subsets of acute myeloid leukemia Mol Med 1998 4: 158–164

    Article  CAS  Google Scholar 

  11. Gazzaniga P, Gradilone A, Vercillo R, Gandini O, Silvestri I, Napolitano M, Albonici L, Vincenzoni A, Gallucci M, Frati L, Agliano AM . Bcl-2/bax mRNA expression ratio as prognostic factor in low-grade urinary bladder cancer Int J Cancer 1996 69: 100–104

    Article  CAS  Google Scholar 

  12. Harima Y, Harima K, Shikata N, Oka A, Ohnishi T, Tanaka Y . Bax and Bcl-2 expressions predict response to radiotherapy in human cervical cancer J Cancer Res Clin Oncol 1998 124: 503–510

    Article  CAS  Google Scholar 

  13. Binder C, Marx D, Binder L, Schauer A, Hiddemann W . Expression of Bax in relation to Bcl-2 and other predictive parameters in breast cancer Ann Oncol 1996 7: 129–133

    Article  CAS  Google Scholar 

  14. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, Wang HG, Zhang X, Bullrich F, Croce CM, Rai K, Hines J, Reed JC . Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses Blood 1998 91: 3379–3389

    CAS  PubMed  Google Scholar 

  15. Bairey O, Zimra Y, Shaklai M, Okon E, Rabizadeh E . Bcl-2, Bcl-X, Bax, and Bak expression in short- and long-lived patients with diffuse large B-cell lymphomas Clin Cancer Res 1999 5: 2860–2866

    CAS  PubMed  Google Scholar 

  16. Daniel PT . Dissecting the pathways to death Leukemia 2000 14: 2035–2044

    Article  CAS  Google Scholar 

  17. Kroemer G . The proto-oncogene Bcl-2 and its role in regulating apoptosis Nat Med 1997 3: 614–620

    Article  CAS  Google Scholar 

  18. Korsmeyer SJ . BCL-2 gene family and the regulation of programmed cell death Cancer Res 1999 59: 1693s–1700s

    CAS  PubMed  Google Scholar 

  19. Haupt Y, Maya R, Kazaz A, Oren M . Mdm2 promotes the rapid degradation of p53 Nature 1997 387: 296–299

    Article  CAS  Google Scholar 

  20. Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J . Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer Nat Med 1996 2: 912–917

    Article  CAS  Google Scholar 

  21. Taubert H, Koehler T, Meye A, Bartel F, Lautenschlager C, Borchert S, Bache M, Schmidt H, Wurl P . mdm2 mRNA level is a prognostic factor in soft tissue sarcoma Mol Med 2000 6: 50–59

    Article  CAS  Google Scholar 

  22. Tsurusawa M, Saeki K, Katano N, Fujimoto T . Bcl-2 expression and prognosis in childhood acute leukemia. Children's Cancer and Leukemia Study Group Pediatr Hematol Oncol 1998 15: 143–155

    Article  CAS  Google Scholar 

  23. Hart SM, Ganeshaguru K, Hoffbrand AV, Prentice HG, Mehta AB . Expression of the multidrug resistance-associated protein (MRP) in acute leukaemia Leukemia 1994 8: 2163–2168

    CAS  PubMed  Google Scholar 

  24. Aguilar-Santelises M, Rottenberg ME, Lewin N, Mellstedt H, Jondal M . Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression Int J Cancer 1996 69: 114–119

    Article  CAS  Google Scholar 

  25. Sturm I, Petrowsky H, Volz R, Lorenz M, Radetzki S, Hillebrand T, Wolff G, Hauptmann S, Dorken B, Daniel PT . Analysis of p53/BAX/p16(ink4a/CDKN2) in esophageal squamous cell carcinoma: high BAX and p16(ink4a/CDKN2) identifies patients with good prognosis J Clin Oncol 2001 19: 2272–2281

    Article  CAS  Google Scholar 

  26. Campos L, Sabido O, Viallet A, Vasselon C, Guyotat D . Expression of apoptosis-controlling proteins in acute leukemia cells Leuk Lymphoma 1999 33: 499–509

    Article  CAS  Google Scholar 

  27. Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, Archimbaud E, Magaud JP, Guyotat D . High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy Blood 1993 81: 3091–3096

    CAS  PubMed  Google Scholar 

  28. Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, Ludwig WD, Henze G, Dorken B, Daniel PT . Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo Leukemia 2000 14: 1606–1613

    Article  CAS  Google Scholar 

  29. Köhler T, Lerche D, Meye A, Weisbrich C, Wagner O . Automated analysis of nucleic acids by quantitative PCR using DNA coated ready-to-use reaction tubes J Lab Med 1999 23: 408–414

    Google Scholar 

  30. Dukas K, Sarfati P, Vaysse N, Pradayrol L . Quantitation of changes in the expression of multiple genes by simultaneous polymerase chain reaction Anal Biochem 1993 215: 66–72

    Article  CAS  Google Scholar 

  31. Finnegan MC, Goepel JR, Hancock BW, Goyns MH . Investigation of the expression of housekeeping genes in non-Hodgkin's lymphoma Leuk Lymphoma 1993 10: 387–393

    Article  CAS  Google Scholar 

  32. Spanakis E . Problems related to the interpretation of autoradiographic data on gene expression using common constitutive transcripts as controls Nucleic Acids Res 1993 21: 3809–3819

    Article  CAS  Google Scholar 

  33. Kern W, Schoch C, Haferlach T, Braess J, Unterhalt M, Wormann B, Buchner T, Hiddemann W . Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities Leukemia 2000 14: 226–231

    Article  CAS  Google Scholar 

  34. Chang M, Raimondi SC, Ravindranath Y, Carroll AJ, Camitta B, Gresik MV, Steuber CP, Weinstein H . Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821 Leukemia 2000 14: 1201–1207

    Article  CAS  Google Scholar 

  35. Salomons GS, Smets LA, Verwijs-Janssen M, Hart AA, Haarman EG, Kaspers GJ, Wering EV, Den Berg DD-V, Kamps WA . Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome Leukemia 1999 13: 1574–1580

    Article  CAS  Google Scholar 

  36. Nuessler V, Stotzer O, Gullis E, Pelka-Fleischer R, Pogrebniak A, Gieseler F, Wilmanns W . Bcl-2, bax and bcl-xL expression in human sensitive and resistant leukemia cell lines Leukemia 1999 13: 1864–1872

    Article  CAS  Google Scholar 

  37. Ong YL, McMullin MF, Bailie KE, Lappin TR, Jones FG, Irvine AE . High bax expression is a good prognostic indicator in acute myeloid leukaemia Br J Haematol 2000 111: 182–189

    Article  CAS  Google Scholar 

  38. Srinivas G, Kusumakumary P, Nair MK, Panicker KR, Pillai MR . Mutant p53 protein, Bcl-2/Bax ratios and apoptosis in paediatric acute lymphoblastic leukaemia J Cancer Res Clin Oncol 2000 126: 62–67

    Article  CAS  Google Scholar 

  39. Karakas T, Maurer U, Weidmann E, Miething CC, Hoelzer D, Bergmann L . High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia Ann Oncol 1998 9: 159–165

    Article  CAS  Google Scholar 

  40. Stoetzer OJ, Nussler V, Darsow M, Gullis E, Pelka-Fleischer R, Scheel U, Wilmanns W . Association of bcl-2, bax, bcl-xL and interleukin-1 beta-converting enzyme expression with initial response to chemotherapy in acute myeloid leukemia Leukemia 1996 10 (Suppl. 3): S18–S22

    Google Scholar 

  41. Kornblau SM, Vu HT, Ruvolo P, Estrov Z, O'Brien S, Cortes J, Kantarjian H, Andreeff M, May WS . BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia Clin Cancer Res 2000 6: 1401–1409

    CAS  PubMed  Google Scholar 

  42. Bargou RC, Daniel PT, Mapara MY, Bommert K, Wagener C, Kallinich B, Royer HD, Dorken B . Expression of the bcl-2 gene family in normal and malignant breast tissue: low bax-alpha expression in tumor cells correlates with resistance towards apoptosis Int J Cancer 1995 60: 854–859

    Article  CAS  Google Scholar 

  43. Huang C, Kohno N, Inufusa H, Kodama K, Taki T, Miyake M . Overexpression of bax associated with mutations in the loop-sheet-helix motif of p53 Am J Pathol 1999 155: 955–965

    Article  CAS  Google Scholar 

  44. Nakano Y, Naoe T, Kiyoi H, Kunishima S, Minami S, Miyawaki S, Asou N, Kuriyama K, Saito H, Ohno R . Poor clinical significance of p53 gene polymorphism in acute myeloid leukemia Leuk Res 2000 24: 349–352

    Article  CAS  Google Scholar 

  45. Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Sloetjes AW, de Witte T, Waksman G, Korsmeyer SJ . Hematopoietic malignancies demonstrate loss-of-function mutations of BAX Blood 1998 91: 2991–2997

    CAS  PubMed  Google Scholar 

  46. Gil J, Yamamoto H, Zapata JM, Reed JC, Perucho M . Impairment of the proapoptotic activity of Bax by missense mutations found in gastrointestinal cancers Cancer Res 1999 59: 2034–2037

    CAS  PubMed  Google Scholar 

  47. Manfredini R, Capobianco ML, Trevisan F, Rauzi F, Barbieri D, Citro G, Tagliafico E, Ferrari S . Antisense inhibition of Bax mRNA increases survival of terminally differentiated HL60 cells Antisense Nucleic Acid Drug Dev 1998 8: 341–350

    Article  CAS  Google Scholar 

  48. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ . Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death Cell 1995 80: 285–291

    Article  CAS  Google Scholar 

  49. Majewski M, Nieborowska-Skorska M, Salomoni P, Slupianek A, Reiss K, Trotta R, Calabretta B, Skorski T . Activation of mitochondrial Raf-1 is involved in the antiapoptotic effects of Akt Cancer Res 1999 59: 2815–2819

    CAS  PubMed  Google Scholar 

  50. Preisler HD, Bi S, Venugopal P, Raza A . Cytokines, molecular biological abnormalities, and acute myelogenous leukemia Leuk Res 1997 21: 299–312

    Article  CAS  Google Scholar 

  51. Andreeff M, Jiang S, Zhang X, Konopleva M, Estrov Z, Snell VE, Xie Z, Okcu MF, Sanchez-Williams G, Dong J, Estey EH, Champlin RC, Kornblau SM, Reed JC, Zhao S . Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid Leukemia 1999 13: 1881–1892

    Article  CAS  Google Scholar 

  52. Hoelzer D, Seipelt G . Acute leukemias and myelodysplastic syndromes. The role of haemopoietic growth factors. Consultant Series No. 6. Gardiner-Caldwell Communications Ltd 1994

Download references

Acknowledgements

The authors gratefully acknowledge the dedicated assistance of all involved doctors, nurses, medical and research assistants, data managers, haematopathologists and cytogeneticists of all hospitals involved in the study. This work was supported by the University of Leipzig and the OSHO study group.

Author information

Authors and Affiliations

  1. Division of Molecular Diagnostics, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical School, Leipzig, Germany

    T Köhler, C Schill & S Borchert

  2. Division of Hematology, Center of Internal Medicine, University of Leipzig Medical School, Leipzig, Germany

    MW Deininger, R Krahl, S Leiblein & D Niederwieser

  3. Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig Medical School, Leipzig, Germany

    D Hasenclever

  4. Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Vienna, Austria

    O Wagner

  5. Roboscreen Gesellschaft für molekulare Biotechnologie mbH, Leipzig, Germany

    T Köhler

Authors
  1. T Köhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Schill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. MW Deininger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Krahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Borchert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Hasenclever
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Leiblein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. O Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Niederwieser
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Köhler, T., Schill, C., Deininger, M. et al. High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML). Leukemia 16, 22–29 (2002). https://doi.org/10.1038/sj.leu.2402340

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402340

Keywords

This article is cited by

Search

Advanced search

Quick links