Mixed-phenotype acute leukaemia with KMT2A rearrangement

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4: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

HAEM4: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.

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

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, 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.

Clinical Features

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Signs and Symptoms	EXAMPLE Asymptomatic (incidental finding on complete blood counts) EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE Cytopenias EXAMPLE Lymphocytosis (low level)

editv4:Clinical Features

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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

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Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

editv4:Immunophenotype

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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)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 20% (COSMIC) EXAMPLE 30% (add reference)	Yes	No	Yes	EXAMPLE The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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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)

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

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

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:1- 159,335,973 [hg38]	EXAMPLE chr7	Yes	Yes	No	EXAMPLE Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:1-145,138,636 [hg38]	EXAMPLE chr8	No	No	No	EXAMPLE Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Not known in this specific subgroup.

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Not known in this specific subgroup.

Epigenomic Alterations

Not known in this specific subgroup.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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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.

Genetic Diagnostic Testing Methods

• Chromosome analysis, FISH

• FISH is needed for cytogenetically cryptic cases with typical immunophenotype

Familial Forms

None

Additional Information

None

Links

KMT2A

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Mixed-phenotype acute leukaemia with KMT2A rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_KMT2A_rearrangement.