Acute Undifferentiated Leukemia

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Primary Author(s)*

Amelia Nakanishi, MD and Shashi Shetty, PhD

Cancer Category/Type

Hematologic malignancy/ Acute leukemia

Cancer Sub-Classification / Subtype

Acute Leukemias of Ambiguous Lineage (WHO 2017)/ Acute Undifferentiated Leukemia (AUL)

Definition / Description of Disease

An acute leukemia with blasts that are immunophenotypically ambiguous for any one hematopoietic lineage. AUL is a diagnosis of exclusion that is incompatible with the presence of features that meet the criteria for inclusion in any of the other AML groups (i.e. AML with Recurrent Genetic Abnormalities, AML with Myelodysplasia-Related Changes, or Therapy-Related Myeloid Neoplasms).

To support an undifferentiated phenotype, AUL requires an immunophenotypic work up that “excludes unusual lineages such as plasmacytoid dendritic cell precursors, natural killer precursors, basophils, and non-hematologic cells”[1].

Synonyms / Terminology

Blast cell leukemia, stem cell leukemia, stem cell acute leukemia, undifferentiated leukemia.

Epidemiology / Prevalence

Very rare; precise frequency unknown.

Clinical Features

In one study of 16 cases of adults with AUL, the median age was 63 years (range: 24-84 years) and patients could achieve clinical remission after allogeneic stem cell transplantation[2]. In previous studies that weakly suggest ALL induction regimens over AML induction regimens, there may be selection bias in the patients who were well enough to be transplant candidates[3].

In children, based on limited clinical information in the literature, AUL has been associated with a poor prognosis[4].

Sites of Involvement

Bone marrow and peripheral blood. AUL is so rare, it is unknown if there is a pattern of other sites of involvement.

Morphologic Features

AUL blast morphology is bland and non-specific. Cytoplasmic granulation and disease defining morphology are absent.


Per WHO 2017, AUL blasts should express no more than one membrane marker for any lineage.

Positive (universal) Precursor stage: HLA-DR, CD34, and/or CD38, CD117, CD133 [5]
Positive (subset) TdT

CD7 (weak positivity) see below.

Negative (universal) Myeloid: MPO

Monocytic: NSE, CD11c, Cd14, CD64, lysozyme, Cd4, CD11b, CD36, NG2 homologue

T cell: cCD3

B cell: cCD22, cCD79a, strong CD19

Megakaryocytic: CD41, CD61, CD42, CD235a

Negative (subset) NA

Additional Description: Blasts are generally positive for  HLA-DR, CD34, and/or CD38.

-CD7 positivity is associated with T cells, but can also be seen in some CD34+ hematopoietic stem cells and is not unexpected in a stem cell leukemia[1].

-See Acute Leukemias of Ambiguous Lineage for assigning lineage assignment.

Chromosomal Rearrangements (Gene Fusions)


Characteristic Chromosomal Aberrations / Patterns

AUL is associated with a high rate of chromosomal abnormalities, but have no characteristic abnormalities[2].

Genomic Gain/Loss/LOH


Gene Mutations (SNV/INDEL)

PHF6 a tumor suppressor gene may have implications in AUL though the evidence is limited.

Other Mutations


Epigenomics (Methylation)


Genes and Main Pathways Involved

Overexpression of BAALC, ERG, and MN1[1].

Diagnostic Testing Methods

Morphology, immunohistochemistry, cytochemistry, flow cytometry, cytogenetics, and next generation sequencing.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

There is evidence that the genes associated with poor prognosis in acute leukemias, BAALC, ERG, and MN1, are also overexpressed in AUL[1].

Familial Forms


Other Information

Although AUL and AML with minimal differentiation are both rare diagnoses, they have similar patient demographics and clinical courses. AUL and AML with minimal differentiation have different molecular abnormalities[2].


Acute Leukemias of Ambiguous Lineage

Mixed Phenotype Acute Leukemia (MPAL), B/Myeloid, Not Otherwise Specified


  1. 1.0 1.1 1.2 1.3 Borowitz MJ, et al., (2017). Acute leukaemias 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. IARC Press: Lyon, France, p182.
  2. 2.0 2.1 2.2 Heesch, Sandra; et al. (2013). "Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization". Annals of Hematology. 92 (6): 747–758. doi:10.1007/s00277-013-1694-4. ISSN 1432-0584. PMID 23412561.
  3. Weinberg, Olga K.; et al. (2019). "Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 32 (9): 1373–1385. doi:10.1038/s41379-019-0263-3. ISSN 1530-0285. PMID 31000771.
  4. Lee, Hyun Gyung; et al. (2019). "Biphenotypic acute leukemia or acute leukemia of ambiguous lineage in childhood: clinical characteristics and outcome". Blood Research. 54 (1): 63–73. doi:10.5045/br.2019.54.1.63. ISSN 2287-979X. PMC 6439300. PMID 30956966.
  5. Hoffman R, et al., (2018) Hematology, basic principles and practice, 7th edition. Elsevier: Philadelphia. (clinical key excerpt)


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