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Mixed phenotype acute leukemia (MPAL) cytogenetics/genomics
Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 30, 2025 · Captured 2026-09-09.
Selected source text with whitespace normalised. This Triangle page is not an NCI PDQ summary. Independent clinical review is pending.
Context: Leukemias / Acute Lymphoblastic Leukemia (ALL)
For acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[193,194] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 2.[106]
| Condition | Definition |
|---|---|
| MPAL = mixed phenotype acute leukemia; NOS = not otherwise specified. | |
| aAdapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[193] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org. | |
| Acute undifferentiated leukemia | Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage |
| MPAL with BCR::ABL1 (t(9;22)(q34;q11.2)) | Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have the (9;22) translocation or the BCR::ABL1 rearrangement |
| MPAL with KMT2A (t(v;11q23)) | Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have a translocation involving the KMT2A gene |
| MPAL, B/myeloid, NOS (B/M MPAL) | Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A |
| MPAL, T/myeloid, NOS (T/M MPAL) | Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A |
| MPAL, B/myeloid, NOS—rare types | Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage |
| Other ambiguous lineage leukemias | Natural killer–cell lymphoblastic leukemia/lymphoma |
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| Lineage | Criteria |
|---|---|
| aAdapted from Arber et al.[106] | |
| bStrong defined as equal to or brighter than the normal B or T cells in the sample. | |
| Myeloid lineage | Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme) |
| T lineage | Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3 |
| B lineage | Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10 |
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The classification system for MPAL includes two entities that are defined by their primary molecular alteration: MPAL with BCR::ABL1 translocation and MPAL with KMT2A rearrangement. The genomic alterations associated with the MPAL, B/myeloid, NOS (B/M MPAL) and MPAL, T/myeloid, NOS (T/M MPAL) entities are distinctive, as described below:
B/M MPAL.
B/M MPAL.
Among 115 MPAL cases for which genomic characterization was performed, 35 (30%) were B/M MPAL. There were an additional 16 MPAL cases (14%) with KMT2A rearrangements, 15 of whom showed a B/myeloid immunophenotype.
B/M MPAL.
Approximately one-half of B/M MPAL cases had rearrangements of ZNF384 with recurrent fusion partners, including TCF3 and EP300. These cases had gene expression profiles indistinguishable from B-ALL cases with ZNF384 rearrangements.[102]
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B/M MPAL.
Approximately two-thirds of B/M MPAL cases had RAS pathway alterations, with NRAS and PTPN11 being the most commonly altered genes.[102]
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B/M MPAL.
Genes encoding epigenetic regulators (e.g., MLLT3, KDM6A, EP300, and CREBBP) are altered in approximately two-thirds of B/M MPAL cases.[102]
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T/M MPAL.
T/M MPAL.
Among 115 MPAL cases for which genomic characterization was performed, 49 (43%) were T/M MPAL.[102] The genomic features of the T/M MPAL cases shared commonalities with those of ETP ALL, suggesting that T/M MPAL and ETP ALL are similar entities along the spectrum of immature leukemias.
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T/M MPAL.
Compared with T-ALL, T/M MPAL showed a lower rate of alterations in the core T-ALL transcription factors (TAL1, TAL2, TLX1, TLX3, LMO1, LMO2, NKX2-1, HOXA10, and LYL1) (63% vs. 16%, respectively).[102] A similar lower rate was also observed for ETP ALL.
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T/M MPAL.
CDKN2A, CDKN2B, and NOTCH1 variants, which are present in approximately two-thirds of T-ALL cases, were much less common in T/M MPAL cases. By contrast, WT1 variants occurred in approximately 40% of T/M MPAL, but in less than 10% of T-ALL cases.[102]
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T/M MPAL.
One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
T/M MPAL. › One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
One such alteration is t(2;14)(q22;q32), which produces an in-frame ZEB2::BCL11B fusion gene that leads to deregulated expression of BCL11B.
T/M MPAL. › One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
Other alterations leading to allele-specific deregulated BCL11B expression include structural variants that juxtapose regulatory sequences of active genes (e.g., ARID1B [chromosome 6], BENC [chromosome 7], and CDK6 [chromosome 7]) upstream or downstream of the BCL11B locus in a process called enhancer hijacking.
T/M MPAL. › One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
Finally, a translocation cannot be identified in about 20% of cases with deregulated BCL11B overexpression. In such cases, amplification of a downstream enhancer, BCL11B enhancer tandem amplification (BETA), leads to BCL11B promoter driven transcription.
T/M MPAL. › One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
There is a high prevalence of FLT3 alterations and JAK/STAT activation in acute leukemias driven by genomic alterations leading to BCL11B overexpression.
T/M MPAL.
RAS and JAK-STAT pathway variants were common in the T/M MPAL and ETP ALL cases, while the PI3K signaling pathway is more commonly altered in T-ALL.[102] For T/M MPAL, the most commonly altered signaling pathway gene was FLT3 (43% of cases). FLT3 variants tended to be mutually exclusive with RAS pathway variants.
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T/M MPAL.
Genes encoding epigenetic regulators (e.g., EZH2 and PHF6) were altered in approximately two-thirds of T/M MPAL cases.[102]
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