Comparative Clinical Pathology

, Volume 26, Issue 2, pp 261–267 | Cite as

Immunophenotype, microRNA expression and cytogenetic characterization of acute leukemias of ambiguous lineage

  • Neda Golchin
  • Elahe Khodadi
  • Seyed Hamid Yaghooti
  • Kaveh Jaseb
  • Mohammad Shahjahani
  • Yousef Tavakolifar
  • Najmaldin Saki


Acute leukemias of ambiguous lineage (ALAL) form a group of leukemias presenting the features of both acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Based on Immunologic Classification of Leukemia (EGIL), these leukemias are recognized as biphenotype acute leukemia (BAL). According to WHO classification and based on immunophenotypic characteristics, ALAL is further categorized to acute undetermined leukemia (AUL), mixed phenotype acute leukemia (MPAL), and other ambiguous lineage leukemias. Immunophenotype and cytogenetic aspects are important in recognition of these leukemias; however, there is limited data about these leukemias. This has resulted in mistreatment of patients. Thanks to the recent advances and introducing the role of microRNAs in regulation of gene expression, a new avenue has been opened in the field of classification and pathogenesis of ambiguous lineage leukemias. MiRNA-based classification can help define myeloid or lymphoid origin of ambiguous lineage leukemias. Taking immunophenotype, cytogenetic, and miRNA profiles into account collectively, a better recognition of the disease is achieved, which results in accurate diagnosis and effective treatment of patients. In this review, we have discussed ambiguous lineage leukemias with regard to microRNA expression, immunophenotype, and cytogenetic aspects.


Acute leukemias of ambiguous lineage Immunophenotype Cytogenetic MicroRNAs 



Acute leukemias of ambiguous lineage


Acute lymphoid leukemia


Acute myeloid leukemia


Immunologic Classification of Leukemia


Biphenotype acute leukemia


Acute undetermined leukemia


Mixed phenotype acute leukemia


Hematopoietic stem cell transplantation


World Health Organization


ETS (erythroblast transformation-specific) related gene


Brain and acute leukemia cytoplasmic


Meningioma (disrupted in balanced translocation)1


Wilms tumor protein 1


Insulin-like growth factor-binding protein 7


FMS-like tyrosine kinase3-internal tandem duplication


not otherwise specified


Terminal deoxynucleotidyl transferase


Minimal residual disease


Anti-killer cell immunoglobulin-like receptors




Nuclear receptor subfamily 2, group F, member 2



We wish to thank all our colleagues in Noor Clinical & Specialty Laboratory

Authors’ contributions

N.S. and S.Y. conceived and revised the manuscript; N.G., E.Kh., Y.T., and M.Sh. wrote the manuscript.

Conflict of interest

The authors declare that they have no competing interests.


  1. Babashah S, Sadeghizadeh M, Rezaie Tavirani M, Farivar S, Soleimani M (2012) Aberrant microRNA expression and its implications in the pathogenesis of leukemias. Cell Oncol 35:317–334CrossRefGoogle Scholar
  2. Bene Marie C (2009) Billinage, ambiguous lineage or mixed lineage: strange leukemias. Haematologica 44:891–893CrossRefGoogle Scholar
  3. Bene MC, Porwit A (2012) Acute leukemias of ambiguous lineage. Semin Diagn Pathol 29:12–18CrossRefPubMedGoogle Scholar
  4. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al (1995) Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 9:1783–86PubMedGoogle Scholar
  5. De Leeuw DC, Ankers WVD, Denkers F, De Menezes RX, Westers TM, Ossenkoppele GJ et al (2013) MicroRNA profiling can classify acute leukemias of ambiguous lineage as either acute myeloid leukemia or acute lymhoid leukemia. Am Assoc Cancer Res 19:2187–2196Google Scholar
  6. Heuser M, Argiropoulos B, Kuchenbauer F, Yung E, Piper J, Fung S (2007) MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 110:1639–47CrossRefPubMedGoogle Scholar
  7. Ichikawa H, Shimizu K, Hayashi Y, Ohki M (1994) An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16; 21) chromosomal translocation. Am Assoc Cancer Res 11:2865–8Google Scholar
  8. Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Wolfgang Blau I et al (2009a) A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 113:6541–48CrossRefPubMedGoogle Scholar
  9. Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Wolfgang Blau I et al (2009b) A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 113:6541–48CrossRefPubMedGoogle Scholar
  10. Kim J, Lee SG, Song J, Kimb SJ, Rhab SY, Lee KA et al (2010) Molecular characterization of alternative SET-NUP214 fusion transcripts in a case of acute undifferentiated leukemia. Cancer Genet Cytogenet 201:73–80CrossRefPubMedGoogle Scholar
  11. LeMaistre A, Childs CC, Hirsch-Ginsberg C, Reuben J, Cork A, Trujillo JM et al (1988) Heterogeneity in acute undifferentiated leukemia. Hematol Pathol 2:79–90PubMedGoogle Scholar
  12. Liu QF, Fan ZP, Wu MQ, Sun J, Wu X-L, Xu D et al (2012) Allo-HSCT for acute leukemia of ambiguous lineage in adults: the comparison between standard conditioning and intensified conditioning regimens. Ann Hematol 92:679–678CrossRefPubMedGoogle Scholar
  13. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–8CrossRefPubMedGoogle Scholar
  14. Manola KN (2013) Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview. B J H 163:24–39CrossRefGoogle Scholar
  15. Mateus E, Pickl WF, Vant Veer M, Morilla R, Swansbury J, Strobl H et al (2008) Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117:3163–71CrossRefGoogle Scholar
  16. Mi S, Lu J, He C, Li Z, Zhang H, Neilly MB et al (2007) MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci U S A 104:19971–6CrossRefPubMedPubMedCentralGoogle Scholar
  17. Myatt SS, Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7:847–59CrossRefPubMedGoogle Scholar
  18. Nishiuchi T, Ohnishi H, Kamada R, Kikuchi F, Shintani T, Waki F et al (2009) Acute leukemia of ambiguous lineage, biphenotype,without CD34, TdT or TCR-rearrangement. Intern Med 48:1437–41CrossRefPubMedGoogle Scholar
  19. Nomdedeu JF, Hoyos M, Carricondo M, Bussaglia E, Estivill C, Esteve J et al (2013) Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML. Leukemia 27:2157–64CrossRefPubMedGoogle Scholar
  20. Owaidah TM, Al BA, Iqbal MA, Elkum N, Roberts GT (2006) Cytogenetics, molecular and ultrastructural characteristics of biphenotypic acute leukemia identified by the EGIL scoring system. Leukemia 20:620–26CrossRefPubMedGoogle Scholar
  21. Owen C, Fitzgibbon J, Paschka P (2010) The clinical relevance of Wilms tumor gene, WT1. Hum Mol Genet 28:13–19Google Scholar
  22. Rubio MT, Dhedin N, Boucheix C, Bourhis H, Reman O, Boiron JM et al (2003) Adult T-biphenotypic acute leukaemia: clinical and biological features and outcome. Br J Haematol 123(5):842–49CrossRefPubMedGoogle Scholar
  23. Rubnitz JE, Onciu M, Pounds S, Shurtleff S, Cao X, Raimondi SC et al (2009) Acute mixed lineage in children: the experience of St Jude Children’s Research Hospital. Blood 113:5083–9CrossRefPubMedPubMedCentralGoogle Scholar
  24. Saki N, Abroun S, Soleimani M, Mortazavi Y, Kaviani S, Arefian E (2013) The roles of mir-146a in the differentiation of Jurkat T-lymphoblasts. Int Soc Hematol 10:1–7Google Scholar
  25. Saki N, Hajizamani S, Rahim F et al (2014a) Association of chromosomal translocation and miRNA expression with the pathogenesis of multiple myeloma. Cell J 16:1–6Google Scholar
  26. Sandra H, Neumann M, Schwartz S, Bartram I, Schlee C, Burmeister T et al (2013) Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization. Ann Hematol 92:747–758CrossRefGoogle Scholar
  27. Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K et al (2001) BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. PNAS 98:13901–6CrossRefPubMedPubMedCentralGoogle Scholar
  28. Uhrberg M (2005) The KIR, gene family: life in the fast lane of evolution. Eur J Immunol 35:10–15CrossRefPubMedGoogle Scholar
  29. Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B et al (1997) Human diversity in killer cell inhibitory receptor genes. Immunity 7:753–63CrossRefPubMedGoogle Scholar
  30. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951CrossRefPubMedGoogle Scholar
  31. Wang Y, Li Z, He C, Wanga D, Yuana X, Chenb J et al (2010) MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis 44:191–7CrossRefPubMedPubMedCentralGoogle Scholar
  32. Weir EG, Ali Ansari-Lari M, Batista DA, Griffin CA, Fuller S, Smith BD et al (2007) Acute bilineal leukemia: a rare disease with poor outcome. Leukemia 21:2264–70CrossRefPubMedGoogle Scholar
  33. Wong GC, Lee LH (2006) Acute biphenotypic leukemia arising in a patient with essential thrombocythemia. Am J Hematol 81:624–26CrossRefPubMedGoogle Scholar
  34. Xu XQ, Wang JM, Lu SQ, Chen L, Yang JM, Zhang WP et al (2009) Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population. Haematologica 7:919–27CrossRefGoogle Scholar
  35. Yuan Y, Kasar S, Underbayev C, Prakash S, Raveche E (2012) MicroRNAs in acute myeloid leukemia and other blood disorders. Leukemia research and treatment 1–11Google Scholar

Copyright information

© Springer-Verlag London 2015

Authors and Affiliations

  • Neda Golchin
    • 1
  • Elahe Khodadi
    • 1
  • Seyed Hamid Yaghooti
    • 2
  • Kaveh Jaseb
    • 1
  • Mohammad Shahjahani
    • 1
  • Yousef Tavakolifar
    • 1
  • Najmaldin Saki
    • 1
  1. 1.Health Research Institute, Research Center of Thalassemia & HemoglobinopathyAhvaz Jundishapur University of Medical SciencesAhvazIran
  2. 2.Department of Medical Laboratory Sciences, School of Allied Medical SciencesAhvaz Jundishapur University of Medical SciencesAhvazIran

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