Acute Leukemias of Ambiguous Lineage

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Primary Author(s)*

Hui Chen, MD, PhD and Jennelle C Hodge, PhD

General Disease Overview / Description of Cancer Category

The category "Acute Leukemias of Ambiguous Lineage", as described in the revised 4th edition of the WHO[1], includes leukemias lacking strong evidence of differentiation along a single lineage (i.e. absence of isolated myeloid, T-cell or B-cell antigens). This category includes acute undifferentiated leukemias, defined by an absence of lineage-specific antigens, and mixed-phenotype acute leukemia (MPAL), characterized by blasts significantly expressing antigens from more than one lineage. MPAL cases can manifest as the presence of multiple separate lineage-specific blast populations (also called bilineage leukemia), a single blast population with antigens of different lineages on the same cells (also called biphenotypic leukemia), or a combination; such blast population characteristics can switch over time or during relapse, and after therapy may even manifest as pure Acute Lymphocytic Leukemia (ALL) or Acute Myeloid Leukemia (AML). The ambiguity of antigen expression typically involves co-existing myeloid with either T-cell or B-cell antigens; B-cell and T-cell antigen co-expression occurs less frequently. Links to related subtypes are listed below in the "WHO Classification Pages" section.

All cases that meet the definition of other WHO categories should be classified as such with a secondary notation that they have a mixed phenotype if applicable[1].

Multiple different genetic alterations occur in this category, most frequently in MPAL. The occurrence of two of these genetic alterations in MPAL are defined by the WHO as their own entities (MPAL with BCR/ABL1 and MPAL with translocations involving KMT2A) based on their frequency and association with distinct features[1].

The diagnosis of ambiguous-lineage leukemias depends on immunophenotyping; flow cytometry is preferred with immunohistochemistry and/or cytochemistry diagnostic in some circumstances. The assignment to myeloid lineage requires positivity of myeloperoxidase (by flow cytometry, immunohistochemistry, or cytochemistry) or monocytic differentiation evidenced in at least two of the markers non-specific esterase, CD11c, CD14, CD64, and lysozyme. Assignment to T-cell lineage requires cytoplasmic CD3 (by flow cytometry or immunohistochemistry) or surface CD3. Assignment to B-cell lineage requires multiple antigens including strong CD19 with strong expression of at least one of the markers CD79a, cytoplasmic CD22, and CD10, or weak CD19 with strong expression of at least two of the markers CD79a, cytoplasmic CD22, and CD10.

WHO Classification Pages (Includes Links to Content)

  1. Acute Undifferentiated Leukemia
  2. Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
  3. Mixed Phenotype Acute Leukemia (MPAL) with t(v;11q23.3); KMT2A Rearranged
  4. Mixed Phenotype Acute Leukemia (MPAL), B/Myeloid, Not Otherwise Specified
  5. Mixed Phenotype Acute Leukemia (MPAL), T/Myeloid, Not Otherwise Specified

Other Related Pages (Includes Links to Content)


Additional Information



  1. 1.0 1.1 1.2 Borowitz MJ, et al., (2017). Acute leukemias of ambiguous lineage, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p180-187.


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*The hierarchical tumour classification structure displayed on this page is reproduced from the WHO Classification of Tumours with permission from the copyright holder, ©International Agency for Research on Cancer.