t(10;11)(p12;q23) KMT2A/NEBL

Identity

ICD-Topo	C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho	9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id	1702

Clinics and Pathology

Disease	Infant acute myeloid leukemia (AML)
Phenotype / cell stem origin	AML-M5.
Epidemiology	Poorly defined, only one case described to date, a 11 month-old boy (Coser et al., 2010).
Prognosis	This infant was treated according to AML-BFM98 backbone adapted protocol and died 1 month later while in the aplastic phase of treatment (Coser et al., 2010).

Cytogenetics

	The probe was hybridized to interphase nuclei and displayed one split hybridization (arrow) signal that indicates translocation with an unknown partner gene (Coser et al., 2010).
Probes	MLL dual color break apart rearrangement probe.

Genes involved and Proteins

Gene Name	KMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location	11q23.3
Dna / Rna	The Mixed-Lineage Leukemia gene consists of 37 exons, encoding a 3969 amino-acid nuclear protein with a molecular weight of nearly 431 kDa.
Protein	431 kDa; contains two DNA binding motifs (a AT hook and Zinc fingers), and a DNA methyl transferase motif; wide expression; nuclear localisation; transcriptional regulatory factor.

Gene Name	NEBL (nebulette)
Location	10p12.31
Note	Nebulette, non-muscle isoform. There exists also a sacomeric isoform of the NEBL gene. Nebulette is the second member of the nebulin family fused to MLL.
Dna / Rna	The Nebulette non-muscle isoform consists of 7 exons, encoding a 270 amino-acid protein with a molecular weight of 31,2 kDa.
Protein	270 aa, 31,2 kDa.

Result of the chromosomal anomaly

Hybrid gene

Note	Fusion gene MLL-NEBL and NEBL-MLL was detected by LDI-PCR (Coser et al., 2010).
	A. Left: Long-distance inverse polymerase chain reaction (LDI-PCR) analysis of both derivatives using genomic DNA. Lane M, size marker; lane 1, LDI-PCR analysis of der(11) showing the wild-type (wt) band and the der(11) band (asterisk); lane 2, LDI-PCR analysis of der(10) showing the wt band and the der(10) band (asterisk). Right: Genomic breakpoint sequence alignment of both derivatives (MLL/NEBL and NEBL/MLL) with respective wt sequences (Coser et al., 2010). B. The genetic fusion of MLL and NEBL in this AML patient occurred within the non-muscle form of the NEBL gene (intron 3) and within the known breakpoint cluster region of MLL (intron 9). The gene structures are indicated and the recombination site is indicated by a dashed line (Emerenciano et al., 2013). C. RT-PCR analyses of MLL-NEBL and NEBL-MLL fusion transcripts (Emerenciano et al., 2013).
Description	In the described patient MLL exons 1-9 are fused to NEBL (non-muscle isoform) exons 4-6 due to translocation between MLL intron 9 and NEBL (non-muscle isoform) intron 3. NEBL (non-muscle isoform) exons 1-3 are fused to MLL exons 10-37 due to translocation between NEBL (non-muscle isoform) intron 3 and MLL intron 10.
Detection	Detection method RT-PCR.

Fusion Protein

	Size and location of functional domains of the MLL wt, NEBL wt, and of the MLL-NEBL fusion protein. AT, AT hook, SNL, subnuclear localization; MT, methyltransferase; BD, binding domain; TAD, transcriptional activation domain; PHD, plant homeo domain; SET, Su(var)3e9; Enhancer-of-zeste, Trithorax; NEBU, nebulette units; SH3, SRC homology 3. (Coser et al., 2010).
Description	The 1582 amino acid big fusion protein retains a major portion of MLL, including those domains known to be essential for leukemic transformation: the AT-hooks and the DNA methyltransferase domain (DNMT) which is fused two nebulin modules, the truncated serine-rich linker region and the SH3 domain of the NEBL protein.

To be noted

Two other studies suggest that the reciprocal fusion gene NEBL-MLL might be of biological importance (Emerenciano et al., 2013; Wächter et al., 2014). Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section.

Bibliography

Nebulette is the second member of the nebulin family fused to the MLL gene in infant leukemia.

Coser VM, Meyer C, Basegio R, Menezes J, Marschalek R, Pombo-de-Oliveira MS.

Cancer Genet Cytogenet. 2010 Apr 15;198(2):151-4. doi: 10.1016/j.cancergencyto.2009.12.013.

PMID 20362230

Functional analysis of the two reciprocal fusion genes MLL-NEBL and NEBL-MLL reveal their oncogenic potential.

Emerenciano M, Kowarz E, Karl K, de Almeida Lopes B, Scholz B, Bracharz S, Meyer C, Pombo-de-Oliveira MS, Marschalek R.

Cancer Lett. 2013 May 10;332(1):30-4. doi: 10.1016/j.canlet.2012.12.023. Epub 2013 Jan 20.

PMID 23340173

Functional characterisation of different MLL fusion proteins by using inducible Sleeping Beauty vectors.

Wachter K, Kowarz E, Marschalek R.

Cancer Lett. 2014 Oct 1;352(2):196-202. doi: 10.1016/j.canlet.2014.06.016. Epub 2014 Jul 9.

PMID 25016062

Citation

This paper should be referenced as such :

C Meyer, M Emerenciano, MS Pombo-de-Oliveira, R Marschalek

t(10;11)(p12;q23) KMT2A/NEBL

Atlas Genet Cytogenet Oncol Haematol. 2015;19(4):308-310.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Anomalies/t1011p12q23ID1702.html

Translocations implicated (Data extracted from papers in the Atlas)

	t(10;11)(p12;q23) KMT2A/NEBL

External links

KMT2A (11q23.3) NEBL (10p12.31)

Mitelman database	t(10;11)(p12;q23)
arrayMap (UZH-SIB Zurich)	Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
TICdb	KMT2A/NEBL  KMT2A (11q23.3) NEBL (10p12.31)

REVIEW articles	automatic search in PubMed
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indexed on : Mon Sep 7 15:08:04 CEST 2020

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