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Relation of BAALC and ERG Gene Expression with Overall Survival in Acute Myeloid Leukemia Cases

  • Published : 2015.12.03

Abstract

Background: The objectives of this study were to evaluate the expression of brain and acute leukemia, cytoplasmic (BAALC) gene and erythroblast transformation-specific related gene (ERG) in de novo cases of acute myeloid leukemia (AML) and identify roles in disease progression and outcome. Materials and Methods: This study included 50 newly diagnosed AML patients, along with 10 apparently healthy normal controls. BAALC and ERG expression was detected in the bone marrow of both patients and controls using real-time RT-PCR. Results: BAALC and ERG expression was detected in 52% of cases but not in any controls. There was a statistically significant correlation between BAALC and ERG gene expression and age (p-value=0.004 and 0.019, respectively). No statistical significance was noted for sex, lymphadenopathy, hepatomegaly, splenomegaly, other hematological findings, immunophenotyping and FAB sub-classification except for ERG gene and FAB (p-value=0.058). A statistical significant correlation was found between response to treatment with ERG expression (p-value=0.028) and age (p-value=0.014). A statistically significant variation in overall survival was evident with patient age, BM blast cells, FAB subgroups, BAALC and ERG expression (p-value=<0.001, 0.045, 0.041, <0.008 and 0.025 respectively). Conclusions: Our results suggest that BAALC and ERG genes are specific significant molecular markers in AML disease progression, response to treatment and survival.

Keywords

References

  1. Baldus CD, Tanner SM, Kusewitt DF, et al (2003). BAALC, a novel marker of human hematopoietic progenitor cells. Exp Hematol, 31, 1051-56.
  2. Baldus CD, Tanner SM, Ruppert AS, et al (2003). BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics. A cancer and leukemia Group B study. Blood, 102, 1613-18. https://doi.org/10.1182/blood-2003-02-0359
  3. Baldus CD, Burmeister T, Martus P, et al (2006). High expression of the ETS transcription factor ERG predicts adverse outcome in acute T-lymphoblastic leukemia in adults. Journal of Clinical Oncology, 24, 4714-20. https://doi.org/10.1200/JCO.2006.06.1580
  4. Baldus CD, Thiede C, Soucek S, et al (2006). BAALC expression and FLT3- internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics, prognostic implications. J Clin Oncol, 24, 790-97. https://doi.org/10.1200/JCO.2005.01.6253
  5. Becker H, Marcucci G, Maharry K, et al (2010). Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene-and micro RNA-expression signatures. A Cancer and Leukemia Group B study. J Clin Oncol, 28, 596-604. https://doi.org/10.1200/JCO.2009.25.1496
  6. Bienz M, Ludwig M, Leibundgut EO, et al (2005). Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res, 11, 1416-24. https://doi.org/10.1158/1078-0432.CCR-04-1552
  7. Bing Xu, Guoshu Chen, Pengcheng Shi, et al (2012). shRNA - Mediated BAALC knockdown affects proliferation and apoptosis in human acute myeloid leukemia cells. Hematology, 17, 35-40. https://doi.org/10.1179/102453312X13221316477499
  8. Dohner H (2005). Implication of the molecular characterization of acute myeloid leukemia. Hematology, Am Soc Hemato Educ Program, 2007, 412-18.
  9. Draghici S, Khatri P, Eklund AC, Szallasi Z (2006). Reliability and reproducibility issues in DNA microarray measurements. Trends Genet, 22, 101-9. https://doi.org/10.1016/j.tig.2005.12.005
  10. Eid MA, Attia M, Abdou S, et al (2010). BAALC and ERG expression in acute myeloid leukemia with normal karyotype: impact on prognosis. International Journal of Laboratory Hematology, 32, 197-205. https://doi.org/10.1111/j.1751-553X.2009.01168.x
  11. Eisfeld AK, Marcucci G, Liyanarachchi S, et al (2012). Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia. Proc Natl Acad Sci USA, 109, 6668-73. https://doi.org/10.1073/pnas.1203756109
  12. Heuser M, Wingen LU, Steinemann D, et al (2005). Gene - expression profiles and their association with drug resistance in adult acute myeloid leukemia. Haematologica, 90, 1484-92.
  13. Jaatinen T, Hemmoranta H, Hautaniemi S, et al (2006). Global gene expression profile of human cord blood - derived CD133+ cells. Stem cells, 24, 631-41. https://doi.org/10.1634/stemcells.2005-0185
  14. Klezovitch O, Risk M, Coleman I, et al (2008). A causal role for ERG in neoplastic transformation of prostate epithelium. PNAS, 105, 2105-10. https://doi.org/10.1073/pnas.0711711105
  15. Kong XT, Ida K, Ichikawa H, et al (1997). Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16; 21)(p11; q22) and identification of a novel transcript. Blood, 90, 1192-99.
  16. Langer C, Radmacher MD, Ruppert AS, et al (2008). High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct geneexpression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia. A Cancer and Leukemia Group B (CALGB) study. Blood, 111, 5371-79. https://doi.org/10.1182/blood-2007-11-124958
  17. Langer C, Marcucci G, Holland KB, et al (2009). Prognostic importance of MN1 transcript levels, and biologic insights from MN1- associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia. A cancer and leukemia group B study. J Clin Oncol, 27, 3198- 204. https://doi.org/10.1200/JCO.2008.20.6110
  18. Lichtman JD, Sternberg DW (2005). The molecular pathology of acute myeloid leukemia. Hematology, Am Soc Hematol Educ Program, 137-42.
  19. Loughran SJ, Kruse EA, Hacking DF, et al (2008). The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol, 9, 810-9.
  20. Marcucci G, Baldus CD, Ruppert AS, et al (2005). Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype. A Cancer and Leukemia Group B study. J Clin Oncol, 23, 9234-42. https://doi.org/10.1200/JCO.2005.03.6137
  21. Marcucci G, Maharry K, Whitman SP, et al (2007). High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia. A Cancer and Leukemia Group B Study. J Clin Oncol, 25, 3337-43. https://doi.org/10.1200/JCO.2007.10.8720
  22. Metzeler KH, Dufour A, Benthaus T, et al (2009). ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays. J Clin Oncol, 27, 5031-38. https://doi.org/10.1200/JCO.2008.20.5328
  23. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD (2007). Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics, are we ready for a prognostically prioritized molecular classification? Blood, 109, 431-48. https://doi.org/10.1182/blood-2006-06-001149
  24. Oikawa T, Yamada T (2003). Molecular biology of the ETS family of transcription factors. Gene, 303, 11-34. https://doi.org/10.1016/S0378-1119(02)01156-3
  25. Santamaria C, Chillon MC, Garcia-Sanz R, et al (2009). BAALC is an important predictor of refractoriness to chemotherapy and poor survival in intermediate-risk acute myeloid leukemia (AML). Ann Hematol, 89, 453-8.
  26. Schwind S, Marcucci G, Maharry K, et al (2010). BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia. A Cancer and Leukemia Group B study. Blood, 116, 5660-69. https://doi.org/10.1182/blood-2010-06-290536
  27. Solomon S, Malkovska V (2005). Acute myeloid leukemia. In: Rodgers GP, Young NS, Eds. Lippincott, Williams and Wilkins pp. 135-50.
  28. Sorensen PH, Lessnick SL, Lopez-Terrada D, et al (1994). A second Ewing's sarcoma translocation, t (21; 22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nature Genetics, 6, 146-51. https://doi.org/10.1038/ng0294-146
  29. Tanner SM, Austin JL, Leone G, et al (2001). BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA, 98, 13901-6. https://doi.org/10.1073/pnas.241525498
  30. Taoudi S, Bee T, Hilton A, et al (2011). ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification. Genes Dev, 25, 251-62. https://doi.org/10.1101/gad.2009211
  31. Toren A, Bielorai B, Jacob-Hirsch J, et al (2005). CD133-positive hematopoietic stem cell "stemness" genes contain many genes mutated or abnormally expressed in leukemia. Stem Cells, 23, 1142-53. https://doi.org/10.1634/stemcells.2004-0317
  32. Vardiman JW, Thiele J, Arber DA, et al (2009). The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood, 114, 937. https://doi.org/10.1182/blood-2009-03-209262
  33. Wang J, Cai Y, Ren C, Ittmann M (2006). Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res, 66, 8347-51. https://doi.org/10.1158/0008-5472.CAN-06-1966
  34. Yang L, Zhou JD, Zhang YY, et al (2015). Overexpression of BAALC, clinical significance in chinese de novo acute myeloid leukemia. Med Oncol, 32, 386-89. https://doi.org/10.1007/s12032-014-0386-9

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