t(9;11)(p21;q23) KMT2A/MLLT3

2016-03-01   Jeroen Knijnenburg  , Jeroen Knijnenburg  

1.Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. b.beverloo@erasmusmc.nl
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Abstract

Review on t(9;11)(p21;q23), with data on clinics, and the genes involved.

Clinics and Pathology

Disease

Acute myeloid leukemia (AML).

Phenotype stem cell origin

Most often found in acute monocytic and myelomonocytic leukaemias, although occasionally also seen in AML with or without maturation (WHO 2008).
M5 most often (especially M5a, M4); both found in de novo and therapy related AML with antitopoisomerase II drugs (epipodophyllotoxins, anthracyclins, actinomycin D).
Immunophenotype typically shows positivity for CD11, CD13, CD15 and CD33, but less often shows positivity for CD14, CD34 and lymphoid markers.

Epidemiology

May occur at any age, but is more common in children, being present in 5-12% of paediatric and 1-2% of adult AML, and equally common in males and females.

Clinics

Organomegaly, frequent central nervous system (CNS) involvement, especially in de novo cases; no preceding myelodysplastic phase, unlike classic therapy related AML with chromosome 5 and/or 7 involvement, short interval from initial drug therapy (may even be of 1-2 yrs). Patients may present with disseminated intravascular coagulation and may have tissue infiltration.

Cytology

Absence of trilineage dysplasia, unlike classic therapy related AML.

Prognosis

Survival is described as poor to intermediate, being superior to AML with other KMT2A translocations.

Cytogenetics

Cytogenetics morphological

May easily be overlooked. Previously described as t(9;11)(p22;q23) based on band estimation, but nowadays it is known that MLLT3 is located in 9p21.3 based on molecular positioning.

Cytogenetics molecular

FISH or RT-PCR is indicated in cases with poor chromosome morphology or in cases where the translocation is expected in cases based on morphology, immunophenotype or clinical presentation.

Additional anomalies

None in 70% of cases, +8 in 20%, less frequently: additional trisomies of chromosome 6, 19 or 21.

Variants

Complex 3 way translocations t(9;11;Var) involving a (variable) third chromosome and insertions have been described, and showed that der(11) is the crucial on

Genes Involved and Proteins

Gene name
MLLT3 (myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 3)
Location
9p21.3
Protein description
Contains a nuclear targeting sequence; transcriptional activator; nuclear localisation.
Gene name
KMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location
11q23.3
Protein description
Contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation.

Result of the Chromosomal Anomaly

Description

5 KMT2A- 3 MLLT3; variable breakpoints.N-term -- AT hook and DNA methyltransferase from KMT2A (1444 amino acids) fused to the 192 C-term amino acids from MLLT3 (as breakpoints are variable, this is only an exemple); 180 kDa.

Expression localisation

Nuclear localisation.

Highly cited references

Pubmed IDYearTitleCitations
348302512021Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).86
365558522022An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene.82
393290742024Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia.75
398349442024Loss of SMAD1 in acute myeloid leukemia with KMT2A::AFF1 and KMT2A::MLLT3 fusion genes.72
370199722023Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.71
368431142023Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes.70
297205852018De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.70
333757732022Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis.69
393800022024The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency.68
334198972021Therapy-induced Deletion in 11q23 Leading to Fusion of KMT2A With ARHGEF12 and Development of B Lineage Acute Lymphoplastic Leukemia in a Child Treated for Acute Myeloid Leukemia Caused by t(9;11)(p21;q23)/KMT2A-MLLT3.66
357933922022In vivo genome-wide CRISPR screening in murine acute myeloid leukemia uncovers microenvironmental dependencies.65
324148482021Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia.60
351537692021Novel Compounds Synergize With Venetoclax to Target KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.60
390939532024The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.58
338037392021Induction of AML Preleukemic Fusion Genes in HSPCs and DNA Damage Response in Preleukemic Fusion Gene Positive Samples.58
358848342022Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group.51
330202822020Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.50
371139892023Whole transcriptome sequencing reveals HOXD11-AGAP3, a novel fusion transcript in the Indian acute leukemia cohort.46
365857872023Discovery of fusion circular RNAs in leukemia with KMT2A::AFF1 rearrangements by the new software CircFusion.45
398585092025Lipopolymers as the Basis of Non-Viral Delivery of Therapeutic siRNA Nanoparticles in a Leukemia (MOLM-13) Model.44
353267052022CDK6 Degradation Is Counteracted by p16(INK4A) and p18(INK4C) in AML.42
389653702024Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study.40
382264142024Enhancer-activated RET confers protection against oxidative stress to KMT2A-rearranged acute myeloid leukemia.39
364523492022Analytical study of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1(p210) , and KMT2-MLLT3 in Mexican children with acute myeloid leukemia: A multicenter study of the Mexican interinstitutional group for the identification of the causes of childhood leukemia (MIGICCL).39
266488362015Cytogenetic and Molecular Findings in Children with Acute Lymphoblastic Leukemia: Experience of a Single Institution in Argentina.38
384279242024Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC).37
386212002024Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia.35
356771552022The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression.35
341344722022RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells.32
318071812019An extra chromosome 9 derived from either a normal chromosome 9 or a derivative chromosome 9 in a patient with acute myeloid leukemia positive for t(9;11)(p21.3;q23.3): A case report.30
359188242022Fusion transcript analysis reveals slower response kinetics than multiparameter flow cytometry in childhood acute myeloid leukaemia.27
343303162021Mature B cell acute lymphoblastic leukaemia with KMT2A-MLLT3 transcripts in children: three case reports and literature reviews.26
381435342023A single scalp nodule as the first presentation of acute lymphoblastic leukemia (KMT2A::MLLT3) in a healthy-appearing infant: a case report.21
334696882021Umbilical cord blood transplantation can overcome the poor prognosis of KMT2A-MLLT3 acute myeloid leukemia and can lead to good GVHD-free/relapse-free survival.20
359333382022Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements.19
333037092020Changing the frequency and spectra of chromosomal aberrations in Korean patients with acute leukemia in a tertiary care hospital.19
341205952021Novel combined variants of WT1 and TET2 in a refractory and recurrent AML patient.16
309530312019FLT3(N676K) drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis.15
354670572022PAX5 alterations in an infant case of KMT2A-rearranged leukemia with lineage switch.15
381625852024Acute myeloid leukemia cutis with KMT2A::MLLT3 fusion presenting with leonine facies.10
317454202019KMT2A-MLLT3 AML Masquerading as JMML may Disguise Fatal Leukemia.8
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338718952021A case of KMT2A-MLLT3 fusion-positive mature B-cell acute lymphoblastic leukemia.0
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396263552025TIFAB modulates metabolic pathways in KMT2A::MLLT3-induced AML through HNF4A.0
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Bibliography

No bibliography items were found for this article.

Summary

Fusion gene

KMT2A/MLLT3 KMT2A (11q23.3) MLLT3 (9p21.3) TIC
Atlas Image
t(9;11)(p21;q23) KMT2A/MLLT3 G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top 2 rows), Courtesy Diane H Norback, Eric B Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (rows 3 to 6); Courtesy  Adriana Zamecnikova (rows 7 and 8); R-banding (right): top: - Courtesy Pascale Cornillet-Lefebvre and Stu00e9phanie Struski, center top: t(9;11)+der(9)t(9;11) - Courtesy Christiane Charrin; bottom 2: - Courtesy Hossein Mossafa. FISH: u201cRedu201d chromosomes - Courtesy Pascale Cornillet-Lefebvre and Stu00e9phanie Struski. The probe is MLL; one signal is on the normal 11, one signal on the der(11), and one signal (arrow) on the der(9); pale blue chromosomes - Courtesy Hossein Mossafa (AN: abnormal). (); bottom 3: Hybridization with Kreatech KMT2A/MLLT3 t(9;11) fusion probe (Leica Biosystems, US) showing hybridization on normal (A) and on metaphases with t(9;11) (B,C). - Courtesy  Adriana Zamecnikova.

Citation

Jeroen Knijnenburg ; Jeroen Knijnenburg

t(9;11)(p21;q23) KMT2A/MLLT3

Atlas Genet Cytogenet Oncol Haematol. 2016-03-01

Online version: http://atlasgeneticsoncology.org/haematological/1001/js/lib/favicon/haematological-explorer/gene-fusions-explorer/

Historical Card

1997-12-01 t(9;11)(p21;q23) KMT2A/MLLT3 by  Jean-Loup Huret,Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France