Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

  • Iqbal, Zafar (CAMS, King Saud Bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia, Hematology, Oncology and Pharmaco-genetic Engineering Sciences (HOPES), Health Sciences Research Laboratory, Faculty of Biological Sciences, Department of Zoology, University of the Punjab, Institute of Molecular Biology & Biotechnology (IMBB) and Centre for Research in Molecular Medicine (CRiMM), the University of Lahore, Department of Biotechnology, University of Sargodha)
  • Published : 2014.04.30


TEL-AML1 fusion oncogene (t 12; 21) is the most common chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL). This translocation is associated with a good prognosis and rarely shows chemotherapeutic resistance to 3-drug based remission induction phase of treatment as well as overall treatment. Thus, the higher the frequency of this fusion oncogene, the easier to manage childhood ALL in a given region with less intensive chemotherapy. Although global frequency of TEL-AML1 has been reported to be 20-30%, a very low frequency has been found in some geographical regions, including one study from Lahore, Punjab, Pakistan and others from India. The objective of present study was to investigate if this low frequency of TEL-AML1 in pediatric ALL is only in Lahore region or similar situation exists at other representative oncology centers of Pakistan. A total of 167 pediatric ALL patients were recruited from major pediatric oncology centers situated in Lahore, Faisalabad, Peshawar and Islamabad. Patients were tested for TEL-AML1 using nested reverse transcription polymerase chain reaction (RT-PCR). Only 17 out of 167 (10.2%) patients were found to be TEL-AML1 positive. TEL-AML1+ALL patients had favorable prognosis, most of them (82.4%, 14/17) showing early remission and good overall survival. Thus, our findings indicate an overall low frequency of TEL-AML1 in Pakistan pediatric ALL patients, in accordance with lower representation of this prognostically important genetic abnormality in other less developed countries, specifically in south Asia, thus associating it with poor living standards in these ethnic groups. It also indicates ethnic and geographical differences in the distribution of this prognostically important genetic abnormality among childhood ALL patients, which may have a significant bearing on ALL management strategies in different parts of the world.


  1. Armstrong SA, Look AT (2005). Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol, 23, 6306-15
  2. Awan T, Iqbal Z, Aleem A, et al (2012). Five most common prognostically important fusion oncogenes are detected in the majority of Pakistani pediatric acute lymphoblastic leukemia patients and are strongly associated with disease biology and treatment outcome. Asian Pac J Cancer Prev, 13, 5469-75.
  3. Bain BJ (2010). Leukemia diagnosis. 4th ed. Wiley-Blackwell publishing, UK.
  4. Belurkar S, Mantravadi H, Manohar C, et al (2013). Correlation of morphologic and cytochemical diagnosis with flowcytometric analysis in acute leukemia. J Cancer Res Ther, 9, 71-9.
  5. Bhojwani D, Pei D, Sandlund JT, et al (2013). ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia, 26, 265-70.
  6. Borkhardt A, Cazzaniga G, Viehmann S, et al (1997). Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster study group. Blood, 90, 571-7.
  7. Cheok MH, Evans WE (2006). Acute lymphoblastic leukemia:a modelfor the pharmacogenomics of cancer therapy. Nat Rev Cancer, 6, 117-29.
  8. Chung HY, Kim KH, Jun KR, et al (2010). Prognostic significance of TEL/AML1 rearrangement and its Additional genetic changes in Korean childhood precursor B-acute lymphoblastic Leukemia. Korean J Lab Med, 30, 1-8.
  9. Coppola D (2010). Mechanism of oncogenesis: an update of Tumorigenesis. springer dordrecht heidelberg, London, New York.
  10. Eguchi-Ishimae M, Eguchi M, Tanaka K, et al (1998). Fluorescence in situ hybridization analysis of 12;21 translocation in Japanese childhood acute lymphoblastic leukaemia. Jpn J Cancer Res, 89, 783-8.
  11. Faiz M, Qazi JI (2010). t(12:21) is underrepresented in childhood B-lineage acute lymphoblastic leukemia in Punjab, Pakistan. J Pediatr Hematol Oncol, 32, 249-51.
  12. Fears S, Vignon C, Bohlander SK, et al (1996). Correlation between the ETV6/CBFA2 (TEL/AML1) fusion gene and karyotypic abnormalities in children with B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer, 17, 127-35.<127::AID-GCC8>3.0.CO;2-7
  13. Garcia-Sanz R, Alaejos I, Orfao A, et al (1999). Low frequency of the TEL/AML1 fusion gene in acute lymphoblastic leukemia in Spain. Br J Haematol, 107, 667-9.
  14. Gill HK, Keoh TS, Dhaliwal JS, et al (2005). TEL-AML1 frequency in multi ethnic Malaysian pediatric acute lymphoblastic leukemia. Cancer Genet Cytogenet, 156, 129-33.
  15. Grech G, Pollacco J, Portelli M, et al (2014). Expression of different functional isoforms in haematopoiesis. Int J Hematol, 99, 4-11.
  16. Harrison CJ (2000). The genetics of childhood acute lymphoblastic leukemia. Bailliere’s Clin Hematol, 3, 427–39.
  17. Hong D, Gupta R, Ancliff P, et al (2008). Initiating and Cancer-Propagating Cells in TEL-AML1-Associated Childhood Leukemia, 319, 336-9.
  18. Iqbal Z (2006). Frequency of chromosomal abnormalities and corresponding fusion oncogenes in acute lympoblastic leukemia (ALL) patients of Pakistan and its implication in differential diagnosis and prognosis of leukemia. Haematologica, 91, 65.
  19. Iqbal Z, Iqbal M, Akhter T (2007). Frequency of BCR-ABL fusion oncogene in Pakistani childhood acute lymphoid leukemia (ALL) patients reflects ethnic differences in molecular genetics of ALL. J Pediatr Hematol Oncol, 29, 585.
  20. Iqbal Z, Tanveer A (2006). Incidence of different fusion oncogenes in acute lympoblastic leukemia (ALL) patients from pakistan: possible implication indifferential diagnosis, prognosis, treatment and management of ALL. Haematologica, 91, 64.
  21. Jamil A, Theil KS, Kahwash S, et al (2000). TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet, 122, 73-8.
  22. Jefford CE, Irminger-Finger I (2006). Mechanisms of chromosome instability in cancers. Crit Rev Oncol Hematol, 59, 1-14.
  23. Jemal A, Siegel R, Ward E, et al (2008). Cancer Statistics. Cancer J Clin, 58, 71-96.
  24. Kwong YL, Wong KF (1997). Low frequency of TEL-AML1 in adult acute lymphoblastic leukemia. Cancer Genet Cytogenet, 98, 137-8.
  25. Lazarus H, Laughlin M (2010). Allogenic stem cell transplantation:Allogenic ematopoietic stem cell transplantation in Pediatric Acute Lymphoblastic Leukemia. 2nded. Humana Press, London.
  26. Lazic J, Tosic N, Dokmanovic L, et al (2010). Clinical features of the most common fusion genes in childhood acute lymphoblastic leukemia. Medical Oncology, 27, 449-53.
  27. Lewis EB (1963). Leukemia, multiple myeloma, and aplastic anemia in american radiologists. Science, 142, 1492-4.
  28. Li BE, Gan T, Meyerson M, et al (2012). Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells. Blood, 122, 2039-46.
  29. Liang DC, Chou TB, Chen JS, et al (1996). High incidence of TEL/AML1 fusion resulting from a cryptic t (12;21) in childhood B-lineage acute lymphoblastic leukemia in Taiwan. Leukemia, 10, 991-3.
  30. Loh ML, Silverman LB, Young ML, et al (1998). Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia. Blood, 92, 4792-97.
  31. Magalhaes IQ, Pombo-De-Oliveira MS, Bennett CA, et al (2000). TEL AML1fusion gene frequency in paediatric acute lymphoblastic leukemia in Brazil. Br J Haematol, 111, 204-7.
  32. Mangolini M, de Boer J, Walf-Vorderwulbecke V, et al (2013). STAT3 mediates oncogenic addiction to TEL-AML1 in t (12;21) acute lymphoblastic leukemia. Blood, 122, 542-9.
  33. Mazloumi SH, Madhumathi DS, Appaji L, Prasannakumari (2012). Combined study of cytogenetics and fluorescence in situ hybridization (FISH) analysis in childhood acute lymphoblastic leukemia (ALL) in a tertiary cancer centre in South India. Asian Pac J Cancer Prev, 13, 3825-7.
  34. Mesquita DR, Cordoba JC, Magalhaes IQ, et al (2009). Molecular and chromosomal mutations among children with B-lineage lymphoblastic leukemia in Brazil’s Federal District. Genet Mol Res, 8, 345-53.
  35. Papadhimitriou S, Paterakis GS, Parcharidou A, et al (2008). TEL-AML1 acute lymphoblastic leukemia in greek pediatric population. Pediatrics, 121, 111-2.
  36. Prasanthi S, Kranthi T, Bharani NLS, et al (2010). Cancer vaccines: a mile stone in cancer therapy. Intl J Biotech Biochem, 6, 259-69.
  37. Pui C, Robison LL, Look AT (2008). Acute lymphoblastic leukemia. The Lancet, 371, 1030-43.
  38. Rahman SA, Mohadess Ardabili SM, Aghazadeh A, et al (2006). Investigation of TEL-AML1 and BCR-ABL fusion oncogenes in patients affected by acute Lymphoblastic leukemia using interphase in situ Hyberdization. J Sc, Islamic Rep Iran, 17, 17-5.
  39. Riccio CA, Sullivan JR, Cohen MJ (2010). Neuropsychological assessment and Intervention for childhood and adolescent disorder. John Wiley and sons, Inc., Hoboken, New Jersey.
  40. Sabir N, Iqbal Z, Aleem A, et al (2012). Prognostically significant fusion oncogenes in Pakistani patients with adult acute lymphoblastic leukemia and their association with disease biology and outcome. Asian Pac J Cancer Prev, 13, 3349-55.
  41. Senyuk V, Zhang Y, Liu Y, et al (2012) Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis. Proc Natl Acad Sci USA, 110, 5594-9.
  42. Shaker HM, Sidhom IA, El-Attar IA (2001). Frequency and clinical relevance of TEL-AML1 fusion gene in childhood acute lymphoblastic Leukemia in Egypt. Journal of the Egyptian Nat. Cancer Inst, 13, 9-18.
  43. Sokol L, Loughran TP (2006). Large granular lymphocyte Leukemia. The Oncologist, 11, 263-73.
  44. Takahashi Y, Horibe K, Kiyoi H, et al (1998). Prognostic significance of TEL/AML1 fusion transcript in childhood B-precursor acute lymphoblastic leukemia. J Ped Hematol Oncol, 20, 190-5.
  45. Tsang KS, Li CK, Chik KW, et al (2001). TEL/AML1 rearrangement and the prognostic significance in childhood acute lymphoblastic leukemia in Hong Kong. Am J Hematol, 68, 91-8.
  46. Tsuzuki S, Seto M (2013). TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice. Stem Cells, 31(2), 236-47.
  47. Uphoff CC, Macleod RA, Denkmann SA, et al (1997). Occurrence of TEL-AML1 fusion resulting from (12;21) translocation in human early B lineage leukemia cell lines. Leukemia, 11, 441-7.
  48. Urayama KY, Thompson PD, Taylor M, et al (2013). Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic Leukemia: a review of the evidence. Front Oncol, 12, 3-300.
  49. van Dongen JJM, Macintyre EA, Gabert JA, et al (1999). Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia, 13, 1901-28.
  50. Voute PA, Barrett A, Stevens MCG, et al (2005). Cancer in Children; Clinical Management. 5th ed. Oxford university press, New York.
  51. Wiemels J (2012). Perspectives on the causes of childhood leukemia Chem Biol Interact, 196, 59-67.
  52. Wiemels JL, Greaves M (1999). Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer Res, 59, 4075.
  53. Woerden NLR, Pieters R, Loonen AH, et al (2000). TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia. Blood, 96, 1094-99.
  54. Zaza G, Yang W, Kager L, et al (2004). Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. Blood, 104, 1435-41.
  55. Zelent A, Greaves M, Enver T (2004). Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukemia. Oncogene, 23, 4275-83.

Cited by

  1. Allogeneic Hemopietic Stem Cell Transplants for the Treatment of B Cell Acute Lymphocytic Leukemia vol.15, pp.15, 2014,
  2. Associations between AT-rich Interactive Domain 5B gene Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia: a Meta-analysis vol.15, pp.15, 2014,
  3. Importance of FISH combined with Morphology, Immunophenotype and Cytogenetic Analysis of Childhood/Adult Acute Lymphoblastic Leukemia in Omani Patients vol.16, pp.16, 2015,
  4. Low Frequency of ETV6-RUNX1 (t 12; 21) in Saudi Arabian Pediatric Acute Lymphoblastic Leukemia Patients: Association with Clinical Parameters and Early Remission vol.16, pp.17, 2015,
  5. Multiplex RT-PCR Assay for Detection of Common Fusion Transcripts in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Cases vol.17, pp.2, 2016,
  6. Gastric carcinoma subsequent to myelodysplastic syndrome with t (1; 19) chromosome translocation vol.97, pp.30, 2018,