Mixed Phenotype Acute Leukemia (MPAL) with t(v;11q23.3); KMT2A Rearranged

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Primary Author(s)*

Tracy Tucker, PhD, FCCMG

Cancer Category/Type

Acute Myeloid Leukemia

Acute Leukemias of Ambiguous Lineage

Cancer Sub-Classification / Subtype

Mixed-phenotype acute leukemia with t(v;11q23.3); KMT2A-rearranged

Definition / Description of Disease

Mixed-phenotype acute leukemia (MPAL) with t(v;11q23.3) results in KMT2A rearrangement with a number of different fusion partners and defines a subtype of MPAL, which are leukemias in which the blast cells show no clear differentiation along a single lineage and instead have both myeloid and lymphoid immunophenotypic markers[1].

KMT2A is commonly rearranged with 4q21.2 (AFF1), although other loci have been reported including 9p21, 9p22,10p12 and 19p13[2][3].

Synonyms / Terminology

Mixed-phenotype acute leukemia with t(v;11q23); MLL rearranged

Mixed phenotype acute leukemia with MLL rearranged

Epidemiology / Prevalence

MPAL accounts for 2-5% of all acute leukemias[2], and the t(v;11q23) is one of two genetically defined entities in MPAL. MPAL with t(v;11q23) has been reported in both the adult and pediatric population[2][3].

Clinical Features

MPAL with t(v;11q23) patients have a similar presentation to other patients with acute leukemia, and likely present similarly to patients with other acute leukemias with KMT2A rearrangement that have a high white blood cell count.

Sites of Involvement

Bone marrow

Morphologic Features

• Blasts must constitute 20% of all nucleated cells, but not necessarily of each distinct lineage.

• Blasts are dimorphic - resembling both lymphoblasts and myeloblasts.

Immunophenotype

The diagnosis of MPAL rests on the immunophenotypic features of blasts rather than morphology and flow cytometry.

The following are criteria for assigning more than one lineage to a single blast population:

• Myeloid lineage – MPO by flow cytometry, immunohistochemistry, or cytochemistry OR monocytic differentiation with two of the following: non-specific esterase, CD11c, CD14, CD64, lysozyme

• T-cell lineage – cytoplasmic or surface CD3 expression

• B-cell lineage – strong CD19 with one of the following strongly expressed: CD79a, cytoplasmic CD22, CD10 OR weak CD19 with two of the following strongly expressed:CD79a, cytoplasmic CD22, CD10

Chromosomal Rearrangements (Gene Fusions)

Almost all cases have a t(v;11q23) identified by karyotype analysis or a KMT2A break-apart by FISH analysis.

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(4;11)(q21;q23) 3'AFF1 / 5'KMT2A der(11) Most common
t(9;11)(p22;q23) 3’MLLT3 / 5’KMT2A der(11)
t(10;11)(p12;q23) 3’MLLT10 / 5’KMT2A der(11)
t(11;19)(q23;p13.3) 3’MLLT1 / 5’KMT2A der(11)

Characteristic Chromosomal Aberrations / Patterns

May exist as the sole abnormality or with secondary abnormalities. Given the rarity of cases, common secondary abnormalities have not been identified.

Genomic Gain/Loss/LOH

Not known in this specific subgroup.

Gene Mutations (SNV/INDEL)

Not known in this specific subgroup.

Epigenomics (Methylation)

Not known in this specific subgroup.

Genes and Main Pathways Involved

Genes:

KMT2A on 11q23.3 is transcribed from centromere to telomere. It encodes a transcriptional coactivator with two DNA binding motifs (an AT hook, and Zinc fingers), a DNA methyl transferase motif (SET domain), a bromodomain; transcriptional regulatory factor and nuclear localization. When KMT2A is part of a multiprotein complex, the SET domain specifically mediates methylation of Lys-4 of histone H3 (H3K4me) which is a tag for epigenetic activation and mediates acetylation of Lys-16 of histone H4 (H4K16ac).

AFF1 on 4q21.3 is transcribed from centromere to telomere. It encodes a transcription factor that regulates RNA polymerase II-mediated transcription through elongation and chromatin remodeling functions. This gene has been shown to promote the expression of CD133, a plasma membrane glycoprotein required for leukemia cell survival.

MLLT3 on 9p21.3 is transcribed from centromere to telomere. It encodes for a transcription factor that is part of the super-elongation complex (SEC) that increases the catalytic rate of RNA polymerase II transcription by suppressing polymerase pausing.

MLLT10 on 10p12.31 is transcribed from telomere to centromere. It encodes a transcription factor with both zinc finger and leucine zipper motifs.

MLLT1 on 19p13.3 is transcribed from centromere to telomere. It encodes for a transcription factor that is part of the super-elongation complex (SEC) that increases the catalytic rate of RNA polymerase II transcription by suppressing polymerase pausing.


DNA:

• 5' KMT2A - 3' AFF1 has variable breakpoints.

• 5' KMT2A - 3' MLLT3 has variable breakpoints.

• 5' KMT2A - 3' MLLT10 has variable breakpoints, however, given that MLLT10 is transcribed in the opposite direction to KMT2A, most result from a complex rearrangement.

• 5' KMT2A - 3' MLLT1 has variable breakpoints.


Protein:

• 5' KMT2A - 3' AFF1 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to the AFF1 C-terminus on the derivative 11 and is predominantly located in the nucleus. The reciprocal AFF1-KMT2A on the derivative 4 may or may not be expressed.

• 5' KMT2A- 3' MLLT3 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to the MLLT3 C-terminus on the derivative 11 and is predominantly located in the nucleus.

• 5' KMT2A - 3' MLLT10 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to the MLLT10 leucine zipper on the derivative 11 and is predominantly located in the nucleus.

• 5' KMT2A - 3' MLLT1 fusion product consists of the AT hook and DNA methyltransferase from KMT2A fused to most of the MLLT1 gene.


Key cellular pathways:

• The partners listed above are all transcriptional regulators that are widely expressed. Regardless of the partner, the methyltransferase activity is lost in the KMT2A fusion product. Although the exact mechanism has not been fully elucidated, the loss of methyltransferase activity results in epigenetic changes in the genome[4].

Diagnostic Testing Methods

• Chromosome analysis, FISH

• FISH is needed for cytogenetically cryptic cases with typical immunophenotype

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Diagnostic:

• The presence of t(v;11q23) with mixed phenotype immune-profile is diagnostic of this cytogenetic subtype of MPAL.


Prognostic:

• t(v;11q23) MPAL has a poor prognosis, similar to other most other leukemias with KMT2A rearrangements.


Therapeutic target:

• No specific molecular targets

Familial Forms

None

Other Information

None

Links

KMT2A

References

  1. Arber, Daniel A.; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
  2. 2.0 2.1 2.2 Manola, Kalliopi N. (2013). "Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview". British Journal of Haematology. 163 (1): 24–39. doi:10.1111/bjh.12484. ISSN 1365-2141. PMID 23888868.
  3. 3.0 3.1 Yan, Lingzhi; et al. (2012). "Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification". Haematologica. 97 (11): 1708–1712. doi:10.3324/haematol.2012.064485. ISSN 1592-8721. PMC 3487445. PMID 22581002.
  4. Johansson B and Harrison CJ (2009). Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells, 3rd edition. Heim S, Mitelman F, Editors. John Wiley & Sons Inc: Hoboken, New Jersey, p84-87.

Notes

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