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
297205852018De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.18
302035712018KMT2A (MLL) rearrangements observed in pediatric/young adult T-lymphoblastic leukemia/lymphoma: A 10-year review from a single cytogenetic laboratory.12
330202822020Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.10
295325202018Clinicopathological characteristics of de novo and secondary myeloid sarcoma: A monocentric retrospective study.10
302771152019Panoramic view of common fusion genes in a large cohort of Chinese de novo acute myeloid leukemia patients.9
324148482021Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia.5
321755992020Measurable residual disease assessment by qPCR in peripheral blood is an informative tool for disease surveillance in childhood acute myeloid leukaemia.5
323688312020Impact of immunophenotypic characteristics on genetic subgrouping in childhood acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) study L04-16.4
266488362015Cytogenetic and Molecular Findings in Children with Acute Lymphoblastic Leukemia: Experience of a Single Institution in Argentina.3
353267052022CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML.2
333757732022Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis.2
333929752021Pediatric blastic plasmacytoid dendritic cell neoplasm: report of four cases and review of literature.2
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-MLLT3.2
309530312019FLT3N676K drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis.2
288711372018C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation.2
354670572022PAX5 alterations in an infant case of KMT2A-rearranged leukemia with lineage switch.1
341344722022RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells.1
343303162021Mature B cell acute lymphoblastic leukaemia with KMT2A-MLLT3 transcripts in children: three case reports and literature reviews.1
338037392021Induction of AML Preleukemic Fusion Genes in HSPCs and DNA Damage Response in Preleukemic Fusion Gene Positive Samples.1
329921022020First report of t(5;11) KMT2A-MAML1 fusion in de novo infant acute lymphoblastic leukemia.1
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.1
317015572019Establishment and characterization of a DOT1L inhibitor-sensitive human acute monocytic leukemia cell line YBT-5 with a novel KMT2A-MLLT3 fusion.1
307014582019Molecular profiling of adult acute myeloid and lymphoid leukemia in a major referral center in Lebanon: a 10-year experience report and review of the literature.1
359333382022Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements.0
359188242022Fusion transcript analysis reveals slower response kinetics than multiparameter flow cytometry in childhood acute myeloid leukaemia.0
357933922022In vivo genome-wide CRISPR screening in murine acute myeloid leukemia uncovers microenvironmental dependencies.0
348941392022Detection of a Cryptic KMT2A/AFDN Gene Fusion [ins(6;11)(q27;q23q23)] in a Pediatric Patient with Newly Diagnosed Acute Myeloid Leukemia.0
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.0
356771552022The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression.0
355068732022Apparent coexistence of ETV6::RUNX1 and KMT2A::MLLT3 fusions due to a nonproductive KMT2A rearrangement in B-ALL.0
351537692021Novel Compounds Synergize With Venetoclax to Target KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.0
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).0
338273672021Is acute lymphoblastic leukemia with mature B-cell phenotype and KMT2A rearrangements a new entity? A systematic review and meta-analysis.0
341205952021Novel combined variants of WT1 and TET2 in a refractory and recurrent AML patient.0
338718952021A case of KMT2A-MLLT3 fusion-positive mature B-cell acute lymphoblastic leukemia.0
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.0
331508192021KMT2A-rearranged diffuse large B-cell lymphoma in a child: a case report and molecular characterization.0
333037092020Changing the frequency and spectra of chromosomal aberrations in Korean patients with acute leukemia in a tertiary care hospital.0
317454202019KMT2A-MLLT3 AML Masquerading as JMML may Disguise Fatal Leukemia.0
312052232019Primary Cutaneous Diffuse Large B-Cell Lymphoma With KMT2A-MLLT3: An Infantile Case Study.0
287859232017A Case of Acute Myeloid Leukemia with Novel Translocation t(6;11)(p22.2;q23) and Concurrent Insertion ins(11;9)(q23;p21.3p21.3).0
285951952017GAS6 Oncogene and Reverse MLLT3-KMT2A Duplications in an Infant with Acute Myeloid Leukemia and a Novel Complex Hyperdiploid Karyotype: Detailed High-Resolution Molecular Cytogenetic Studies.0

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/case-report-explorer/meetings/humanGenome

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