Acute myeloid leukaemia with KMT2A rearrangement
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with t(9;11)(p21.3;q23.3); KMT2A-MLLT3.
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Primary Author(s)*
Megan Piazza, Ph.D., Yiming Zhong, Ph.D., Shashi Shetty, Ph.D.
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Acute myeloid leukaemia |
| Type | Acute myeloid leukaemia with defining genetic abnormalities |
| Subtype(s) | Acute myeloid leukaemia with KMT2A rearrangement |
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system[1][2].
Synonyms / Terminology
AF9/MLL
Epidemiology / Prevalence
Accounts for 9-12% of pediatric cases of AML and 1- 2% of adult AML cases[3][4]. No gender bias noted.
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 FeaturesThe content below was from the old template. Please incorporate above.Patients may present with disseminated intravascular coagulation (DIC), extramedullary myeloid (monocytic) sarcomas, and/or tissue infiltration involving the gingiva and skin[1].
Sites of Involvement
Bone marrow
Morphologic Features
This subtype may be seen in AML with or without maturation and has a strong association with acute monocytic and myelomonocytic leukemias[1]. The blasts present are typically monoblasts or promonocytes[1]. The monoblasts are large cells that have abundant cytoplasm, which may be moderate to intensely basophilic. The cytoplasm may also show pseudopod formation, scattered and fine azurophilic granules, and vacuoles. The nuclei of the monoblasts are typically round with delicate lacy chromatin and may contain one or more prominent nucleoli. The promonocytes have cytoplasm that is less basophilic and may be more granulated, in addition to the presence of the occasional large azurophilic granules and vacuoles. Mostly these monoblasts and promonocytes are MPO negative by immunohistochemistry. These cells have a more irregularly shaped and delicately convoluted nuclear configuration.
Immunophenotype
| Finding | Marker |
|---|---|
| Positive (universal) | CD33, CD65, CD4, and HLA-DR (children); CD14, CD4, CD11b, CD11c, CD64, CD36, and Lysozyme (adults)[5] |
| Positive (subset) | Neuron-glial antigen 2 (NG2) (children and adults)[6]
CD34, CD117, and CD56 (adult)[5] |
| Negative (universal) | CD13, CD34, and CD14 (children)[7] |
| Negative (subset) | None |
Chromosomal Rearrangements (Gene Fusions)
Put your text here and fill in the table
| 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)The content below was from the old template. Please incorporate above.This AML subtype is classified based on the translocation between chromosomes 9 and 11, specifically t(9;11)(p21.3;q23.3). This translocation leads to the fusion of the 5’ portion of KMT2A at 11q23.3 and the 3’ portion of MLLT3 at 9p21.3. Both reciprocal fusions are expressed, however, the KMT2A-MLLT3 fusion on the derivative chromosome 11 is the candidate oncoprotein as it contains the putative functional domains of both proteins[1][3][8].
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence t(9;11)(p21.3;q23.3) 5'KMT2A / 3'MLLT3 der(11) 1-12% of AML
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
Patients with t(9;11) resulting in a fusion between KMT2A and MLLT3 and ≥20% blasts are diagnosed with AML with t(9;11). AML with t(9;11)(p21.3;q23.3) has an intermediate survival, which is superior to AML with other 11q23 translocations[8][9]. There have been over 50 KMT2A translocation partners identified[10][11] and one of the most common partners is MLLT3[1].
Patients presenting with t(9;11)(p22;q23) and <20% blasts should be monitored closely for more definite evidence of AML.
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.)
| 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/LOHThe content below was from the old template. Please incorporate above.The t(9;11)( p21.3;q23.3) can present with secondary abnormalities, most frequently trisomy of chromosome 8[3][8].
Chromosome Number Gain/Loss/Amp/LOH Region 8 Gain (trisomy) Entire chromosome
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. Do not delete table.)
| 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 / PatternsThe content below was from the old template. Please incorporate above.Not applicable
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)The content below was from the old template. Please incorporate above.NA
Other Mutations
NA
Epigenomic Alterations
Not applicable
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)
| 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 InvolvedThe content below was from the old template. Please incorporate above.The KMT2A (Lysine Methyltransferase 2A) gene encodes a protein that complexes with other proteins and functions to regulate gene transcription through chromatin remodeling. This protein plays a vital role in regulating gene expressing during early development and hematopoiesis. The MLLT3 (Super Elongation Complex Subunit) gene encodes a protein that is an element of the super elongation complex (SEC). The SEC is a complex that plays an essential role in regulating the activity of RNA polymerase II transcription. The fusion protein created, KMT2A-MLLT3, leads to the promotion of transcriptional elongation, activation of genes that would typically be silenced, and thus inhibits hematopoietic cells from properly maturing[12].
Genetic Diagnostic Testing Methods
Karyotype, FISH, RT-PCR
Familial Forms
Not applicable
Additional Information
Not applicable
Links
References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, 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, 136-138.
- ↑ "Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405". Blood. 128 (3): 462–463. 2016. doi:10.1182/blood-2016-06-721662. ISSN 1528-0020. PMID 31659364.
- ↑ 3.0 3.1 3.2 Byrd, John C.; et al. (2002). "Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)". Blood. 100 (13): 4325–4336. doi:10.1182/blood-2002-03-0772. ISSN 0006-4971. PMID 12393746.
- ↑ Forestier, Erik; et al. (2003). "Cytogenetic abnormalities in childhood acute myeloid leukaemia: a Nordic series comprising all children enrolled in the NOPHO-93-AML trial between 1993 and 2001". British Journal of Haematology. 121 (4): 566–577. doi:10.1046/j.1365-2141.2003.04349.x. ISSN 0007-1048. PMID 12752097.
- ↑ 5.0 5.1 Muñoz, L.; et al. (2003). "Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells". Leukemia. 17 (1): 76–82. doi:10.1038/sj.leu.2402708. ISSN 0887-6924. PMID 12529663.
- ↑ Wuchter, C.; et al. (2000). "Detection of acute leukemia cells with mixed lineage leukemia (MLL) gene rearrangements by flow cytometry using monoclonal antibody 7.1". Leukemia. 14 (7): 1232–1238. doi:10.1038/sj.leu.2401840. ISSN 0887-6924. PMID 10914547.
- ↑ Creutzig, U.; et al. (1995). "Clinical significance of surface antigen expression in children with acute myeloid leukemia: results of study AML-BFM-87". Blood. 86 (8): 3097–3108. ISSN 0006-4971. PMID 7579404.
- ↑ 8.0 8.1 8.2 Mrózek, K.; et al. (1997). "Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study". Blood. 90 (11): 4532–4538. ISSN 0006-4971. PMID 9373264.
- ↑ Rubnitz, Jeffrey E.; et al. (2002). "Favorable impact of the t(9;11) in childhood acute myeloid leukemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 20 (9): 2302–2309. doi:10.1200/JCO.2002.08.023. ISSN 0732-183X. PMID 11981001.
- ↑ Meyer, C.; et al. (2006). "The MLL recombinome of acute leukemias". Leukemia. 20 (5): 777–784. doi:10.1038/sj.leu.2404150. ISSN 0887-6924. PMID 16511515.
- ↑ Shih, L.-Y.; et al. (2006). "Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement". Leukemia. 20 (2): 218–223. doi:10.1038/sj.leu.2404024. ISSN 0887-6924. PMID 16341046.
- ↑ Mueller, Dorothee; et al. (2009). "Misguided transcriptional elongation causes mixed lineage leukemia". PLoS biology. 7 (11): e1000249. doi:10.1371/journal.pbio.1000249. ISSN 1545-7885. PMC 2774266. PMID 19956800.
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: “Acute myeloid leukaemia with KMT2A rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_KMT2A_rearrangement.