Acute Myeloid Leukemia (AML) with t(9;11)(p21.3;q23.3); KMT2A-MLLT3
Megan Piazza, Ph.D., Yiming Zhong, Ph.D., Shashi Shetty, Ph.D.
- 1 Primary Author(s)*
- 2 Cancer Category/Type
- 3 Cancer Sub-Classification / Subtype
- 4 Definition / Description of Disease
- 5 Synonyms / Terminology
- 6 Epidemiology / Prevalence
- 7 Clinical Features
- 8 Sites of Involvement
- 9 Morphologic Features
- 10 Immunophenotype
- 11 Chromosomal Rearrangements (Gene Fusions)
- 12 Characteristic Chromosomal Aberrations / Patterns
- 13 Genomic Gain/Loss/LOH
- 14 Gene Mutations (SNV/INDEL)
- 15 Epigenomics (Methylation)
- 16 Genes and Main Pathways Involved
- 17 Diagnostic Testing Methods
- 18 Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
- 19 Familial Forms
- 20 Other Information
- 21 Links
- 22 References
- 23 Notes
Acute Myeloid Leukemia
Cancer Sub-Classification / Subtype
Acute myeloid leukemia with t(9;11)(p21.3;q23.3) resulting in KMT2A(MLL)-MLLT3(AF9) fusion
Definition / Description of Disease
Synonyms / Terminology
Epidemiology / Prevalence
Patients may present with disseminated intravascular coagulation (DIC), extramedullary myeloid (monocytic) sarcomas, and/or tissue infiltration involving the gingiva and skin.
Sites of Involvement
This subtype may be seen in AML with or without maturation and has a strong association with acute monocytic and myelomonocytic leukemias. The blasts present are typically monoblasts or promonocytes. 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.
|Positive (universal)||CD33, CD65, CD4, and HLA-DR (children) [5, CD14, CD4, CD11b, CD11c, CD64, CD36, and Lysozyme (adults)|
|Positive (subset)||Neuron-glial antigen 2 (NG2) (children and adults)
CD34, CD117, and CD56 (adult)
|Negative (universal)||CD13, CD34, and CD14 (children)|
Chromosomal Rearrangements (Gene Fusions)
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. The t(9;11)( p21.3;q23.3) can present with secondary abnormalities, most frequently trisomy of chromosome 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|
Characteristic Chromosomal Aberrations / Patterns
Gene Mutations (SNV/INDEL)
Genes and Main Pathways Involved
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.
Diagnostic Testing Methods
Karyotype, FISH, RT-PCR
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
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. There have been over 50 KMT2A translocation partners identified and one of the most common partners is MLLT3.
Patients presenting with t(9;11)(p22;q23) and <20% blasts should be monitored closely for more definite evidence of AML.
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