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.

Cancer Category/Type

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

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

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) [5, 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)

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[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

Characteristic Chromosomal Aberrations / Patterns

Not applicable

Genomic Gain/Loss/LOH

Not applicable

Chromosome Number Gain/Loss/Amp/LOH Region
NONE NONE NONE
NONE NONE NONE

Gene Mutations (SNV/INDEL)

NA

Other Mutations

NA

Epigenomics (Methylation)

Not applicable

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[9].

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[8][10]. There have been over 50 KMT2A translocation partners identified[11][12] 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.

Familial Forms

Not applicable

Other Information

Not applicable

Links

KMT2A

MLLT3

References

  1. 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.
  2. "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. 3.0 3.1 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.
  4. 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. 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.
  6. 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.
  7. 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. 8.0 8.1 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.

Notes

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