| Written | 2014-09 | Claus Meyer, Mariana Emerenciano, Maria S Pombo-de-Oliveira, Rolf Marschalek |
| Institute of Pharmaceutical Biology/ZAFES/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University of Frankfurt, Max-von-Laue Str. 9, Frankfurt/Main, Germany (CM, RM); Hematology-Oncology Pediatric Program, CPq Instiuto Nacional de Cancer, Rio de Janeiro, Brazil (ME, MSPO) |
| 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 |
| 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. |
 | |
| 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: |
| 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 |
| REVIEW articles | automatic search in PubMed |
| Last year articles | automatic search in PubMed |
| All articles | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Jul 9 10:12:15 CEST 2018 |
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