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.

  • Review
  • Published:

Mixed-phenotype acute leukemia: historical overview and a new definition

Leukemia volume 24, pages 1844–1851 (2010)Cite this article

Subjects

Abstract

Acute leukemia with a mixed phenotype is a rare disease and comprises 2–5% of all acute leukemias. These disorders have been known historically by a variety of names, such as mixed lineage leukemia, bilineal leukemia and biphenotypic leukemia, and the criteria for diagnosis have often been arbitrary. The scoring criteria proposed by the European Group for the Immunological Characterization of Leukemias represented a major attempt to define this disorder. However, the relative weight given to some markers and the lack of lineage specificity of most markers have raised questions regarding the significance of this approach. In 2008, the World Health Organization classification of hematopoietic and lymphoid tumors proposed a simpler diagnostic algorithm, which relies on fewer and more lineage-specific markers to define mixed-phenotype acute leukemia (MPAL). MPAL with t(9;22) and MLL rearrangement have been separated. Several studies have suggested that patients with acute leukemia of mixed phenotype have a worse clinical outcome when compared with matched controls with acute myeloid leukemia or acute lymphoblastic leukemia. Further studies are needed to confirm the significance of MPAL as currently defined, to determine a standardized treatment approach and to better understand the biological and clinical aspects of this disease.

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

Similar content being viewed by others

References

  1. Weir EG, Borowitz MJ . Acute leukemias of ambiguous lineage. In: Jaffe ES, Harris NL, Vardiman JW, Campo E, Arber DA (eds). Hematopathology. Elsevier: Philadelphia, 2010.

    Google Scholar 

  2. Weir EG, Ali Ansari-Lari M, Batista DA, Griffin CA, Fuller S, Smith BD et al. Acute bilineal leukemia: a rare disease with poor outcome. Leukemia 2007; 21: 2264–2270.

    Article  CAS  PubMed  Google Scholar 

  3. Kita K, Nakase K, Miwa H, Masuya M, Nishii K, Morita N et al. Phenotypical characteristics of acute myelocytic leukemia associated with the t(8;21)(q22;q22) chromosomal abnormality: frequent expression of immature B-cell antigen CD19 together with stem cell antigen CD34. Blood 1992; 80: 470–477.

    CAS  PubMed  Google Scholar 

  4. Hurwitz CA, Raimondi SC, Head D, Krance R, Mirro Jr J, Kalwinsky DK et al. Distinctive immunophenotypic features of t(8;21)(q22;q22) acute myeloblastic leukemia in children. Blood 1992; 80: 3182–3188.

    CAS  PubMed  Google Scholar 

  5. Adriaansen HJ, te Boekhorst PA, Hagemeijer AM, van der Schoot CE, Delwel HR, van Dongen JJ . Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression. Blood 1993; 81: 3043–3051.

    CAS  PubMed  Google Scholar 

  6. Khalidi HS, Medeiros LJ, Chang KL, Brynes RK, Slovak ML, Arber DA . The immunophenotype of adult acute myeloid leukemia: high frequency of lymphoid antigen expression and comparison of immunophenotype, French-American-British classification, and karyotypic abnormalities. Am J Clin Pathol 1998; 109: 211–220.

    Article  CAS  PubMed  Google Scholar 

  7. Khalidi HS, Chang KL, Medeiros LJ, Brynes RK, Slovak ML, Murata-Collins JL et al. Acute lymphoblastic leukemia. Survey of immunophenotype, French-American-British classification, frequency of myeloid antigen expression, and karyotypic abnormalities in 210 pediatric and adult cases. Am J Clin Pathol 1999; 111: 467–476.

    Article  CAS  PubMed  Google Scholar 

  8. Childs CC, Hirsch-Ginsberg C, Walters RS, Andersson BS, Reuben J, Trujillo JM et al. Myeloid surface antigen-positive acute lymphoblastic leukemia (My+ ALL): immunophenotypic, ultrastructural, cytogenetic, and molecular characteristics. Leukemia 1989; 3: 777–783.

    CAS  PubMed  Google Scholar 

  9. Bene MC . Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias!. Hematologica 2009; 94: 891–893.

    Article  Google Scholar 

  10. McGraw TP, Folds JD, Bollum FJ, Strass SA . Terminal deoxynucleotidyl transferase-positive acute myeloblastic leukemia. Am J Hematol 1981; 10: 251–258.

    Article  CAS  PubMed  Google Scholar 

  11. Scamurra DO, Davey FR, Nelson DA, Kurec AS, Goldberg J . Acute leukemia presenting with myeloid and lymphoid cell markers. Ann Clin Lab Sci 198; 13: 396–502.

    Google Scholar 

  12. Mirro J, Zipf TF, Pui CH, Kitchingman G, Williams D, Melvin S et al. Acute mixed lineage leukemia: clinicopathologic correlation and prognostic significance. Blood 1985; 66: 1115–1123.

    CAS  PubMed  Google Scholar 

  13. Catovsky D, Matutes E, Buccheri V, Shetty V, Hanslip J, Yoshida N et al. A classification of acute leukemia for the 1990s. Ann Hematol 1991; 62: 16–21.

    Article  CAS  PubMed  Google Scholar 

  14. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9: 1783–1786.

    CAS  PubMed  Google Scholar 

  15. Bene MC, Bernier M, Casasnovas RO, Castoldi G, Knapp W, Lanza F et al. The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. Blood 1998; 92: 596–599.

    CAS  PubMed  Google Scholar 

  16. Jaffe E, Harris N, Stein HVJ, Vardiman JW (eds). Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues, 2nd printing, World Health Organization Classification of Tumours. IARC Press: Lyon, France, 2001.

    Google Scholar 

  17. Aribi A, Bueso-Ramos C, Estey E, Estrov Z, O’Brien S, Giles F et al. Biphenotypic acute leukaemia: a case series. Br J Haematol 2007; 138: 213–216.

    Article  PubMed  Google Scholar 

  18. Bagg A . Lineage ambiguity, infidelity, and promiscuity in immunophenotypically complex acute leukemias: genetic and morphologic correlates. Am J Clin Pathol 2007; 128: 545–548.

    Article  PubMed  Google Scholar 

  19. Valbuena JR, Medeiros LJ, Rassidakis GZ, Hao S, Wu CD, Chen L et al. Expression of B cell-specific activator protein/PAX5 in acute myeloid leukemia with t(8;21)(q22;q22). Am J Clin Pathol 2006; 126: 235–240.

    Article  PubMed  Google Scholar 

  20. Chapiro E, Delabesse E, Asnafi V, Millien C, Davi F, Nugent E et al. Expression of T-lineage-affiliated transcripts and TCR rearrangements in acute promyelocytic leukemia: implications for the cellular target of t(15;17). Blood 2006; 108: 3484–3493.

    Article  CAS  PubMed  Google Scholar 

  21. Hashimoto M, Yamashita Y, Mori N . Immunohistochemical detection of CD79a expression in precursor T cell lymphoblastic lymphoma/leukemias. J Pathol 2002; 197: 341–347.

    Article  CAS  PubMed  Google Scholar 

  22. Pilozzi E, Pulford K, Jones M, Müller-Hermelink HK, Falini B, Ralfkiaer E et al. Co-expression of CD79a (JCB117) and CD3 by lymphoblastic lymphoma. J Pathol 1998; 186: 140–143.

    Article  CAS  PubMed  Google Scholar 

  23. Arber DA, Jenkins KA, Slovak ML . CD79 alpha expression in acute myeloid leukemia. High frequency of expression in acute promyelocytic leukemia. Am J Pathol 1996; 149: 1105–1110.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bhargava P, Kallakury BV, Ross JS, Azumi N, Bagg A . CD79a is heterogeneously expressed in neoplastic and normal myeloid precursors and megakaryocytes in an antibody clone-dependent manner. Am J Clin Pathol 2007; 128: 306–313.

    Article  PubMed  Google Scholar 

  25. Arber DA, Snyder DS, Fine M, Dagis A, Niland J, Slovak ML . Myeloperoxidase immunoreactivity in adult acute lymphoblastic leukemia. Am J Clin Pathol 2001; 116: 25–33.

    Article  CAS  PubMed  Google Scholar 

  26. Paietta E, Racevskis J, Bennett JM, Wiernik PH . Differential expression of terminal transferase (TdT) in acute lymphocytic leukaemia expressing myeloid antigens and TdT positive acute myeloid leukaemia as compared to myeloid antigen negative acute lymphocytic leukaemia. Br J Haematol 1993; 84: 416–422.

    Article  CAS  PubMed  Google Scholar 

  27. Borowitz MJ, Bene MC, Harris NL, Porwit A, Matutes E . Acute leukemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2008, pp 150–155.

    Google Scholar 

  28. Khalidi HS, Brynes RK, Medeiros LJ, Chang KL, Slovak ML, Snyder DS et al. The immunophenotype of blast transformation of chronic myelogenous leukemia: a high frequency of mixed lineage phenotype in “lymphoid” blasts and a comparison of morphologic, immunophenotypic, and molecular findings. Mod Pathol 1998; 11: 1211–1221.

    CAS  PubMed  Google Scholar 

  29. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 620–625.

    Article  CAS  PubMed  Google Scholar 

  30. Sevilla DW, Colovai AI, Emmons FN, Bhagat G, Alobeid B . Hematogones: a review and update. Leuk Lymphoma 2010; 51: 10–19.

    Article  PubMed  Google Scholar 

  31. Babusíková O, Zelezníková T, Kirschnerová G, Kankuri E . Hematogones in acute leukemia during and after therapy. Leuk Lymphoma 2008; 49: 1935–1944.

    Article  PubMed  Google Scholar 

  32. Rimsza LM, Larson RS, Winter SS, Foucar K, Chong YY, Garner KW et al. Benign hematogone-rich lymphoid proliferations can be distinguished from B-lineage acute lymphoblastic leukemia by integration of morphology, immunophenotype, adhesion molecule expression, and architectural features. Am J Clin Pathol 2000; 114: 66–75.

    Article  CAS  PubMed  Google Scholar 

  33. Al-Seraihy AS, Owaidah TM, Ayas M, El-Solh H, Al-Mahr M, Al-Ahmari A et al. Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 2009; 94: 1682–1690.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Killick S, Matutes E, Powles RL, Hamblin M, Swansbury J, Treleaven JG et al. Outcome of biphenotypic acute leukemia. Haematologica 1999; 84: 699–706.

    CAS  PubMed  Google Scholar 

  35. Owaidah TM, Al Beihany A, Iqbal MA, Elkum N, Roberts GT . Cytogenetics, molecular and ultrastructural characteristics of biphenotypic acute leukemia identified by the EGIL scoring system. Leukemia 2006; 20: 620–626.

    Article  CAS  PubMed  Google Scholar 

  36. Xu XQ, Wang JM, Lü SQ, Chen L, Yang JM, Zhang WP et al. 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 2009; 94: 919–927.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Thalhammer-Scherrer R, Mitterbauer G, Simonitsch I, Jaeger U, Lechner K, Schneider B et al. The immunophenotype of 325 adult acute leukemias: relationship to morphologic and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination. Am J Clin Pathol 2002; 117: 380–389.

    Article  PubMed  Google Scholar 

  38. Rubnitz JE, Onciu M, Pounds S, Shurtleff S, Cao X, Raimondi SC et al. Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital. Blood 2009; 113: 5083–5089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee JH, Min YH, Chung CW, Kim BK, Yoon HJ, Jo DY et al. Prognostic implications of the immunophenotype in biphenotypic acute leukemia. Leuk Lymphoma 2008; 49: 700–709.

    Article  CAS  PubMed  Google Scholar 

  40. Legrand O, Perrot JY, Simonin G, Baudard M, Cadiou M, Blanc C et al. Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression. Br J Haematol 1998; 100: 147–155.

    Article  CAS  PubMed  Google Scholar 

  41. Wouters BJ, Koss C, Delwel R . Gene expression profiling for improved dissection of acute leukemia: a recently identified immature myeloid/T-lymphoid subgroup as an example. Blood Cells Mol Dis 2008; 40: 395–400.

    Article  CAS  PubMed  Google Scholar 

  42. Buccheri V, Matutes E, Dyer MJS, Catovsky D . Lineage commitment in biphenotypic acute leukemia. Leukemia 1993; 7: 919–927.

    CAS  PubMed  Google Scholar 

  43. Dupret C, Asnafi V, Leboeuf D, Millien C, Ben Abdelali R, Preudhomme C et al. IgH/TCR rearrangements are common in MLL translocated adult AML and suggest an early T/myeloid or B/myeloid maturation arrest, which correlates with the MLL partner. Leukemia 2005; 19: 2337–2338.

    Article  CAS  PubMed  Google Scholar 

  44. Zheng C, Wu J, Liu X, Ding K, Cai X, Zhu W . What is the optimal treatment for biphenotypic acute leukemia? Haematologica 2009; 94: 1778–1780.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pui C-H, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St. Jude Children's Research Hospital. Blood 2004; 104: 2690–2696.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Stanford University Medical Center, Stanford, CA, USA

    O K Weinberg & D A Arber

Authors
  1. O K Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D A Arber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O K Weinberg.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weinberg, O., Arber, D. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia 24, 1844–1851 (2010). https://doi.org/10.1038/leu.2010.202

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.202

Keywords

This article is cited by

Search

Advanced search

Quick links