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TBL1XR1/MECOM fusion

del(3)(q26.2q26.3) TBL1XR1/MECOM

Written2018-04Chrystelle Abdo, Marie Passet, Odile Maarek, Emmanuelle Clappier
Service d'Hématologie biologique, hôpital Saint-Louis, AP-HP; Chrystelle.abdo@aphp.fr; Marie.passet@aphp.fr; Emmanuelle.clappier@aphp.fr

Abstract A novel TBL1XR1/MECOM fusion was identified in a patient with acute undifferentiated leukemia.

Keywords chromosome 3 ; MECOM; TBL1XR1; acute undifferentiated leukemia; deletion 3q26.2q26.32 ; fusion gene

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9801/3 Acute undifferentiated leukaemia
Atlas_Id 1823

Clinics and Pathology

Disease Acute undifferentiated leukaemia (classified in acute leukaemias of ambiguous lineage)
Phenotype / cell stem origin This leukemia was CD34+high, CD38+ and CD117+/- but negative for all lineage specific markers (cMPO-, CD13-, CD33-, CD7-, cCD3-, cCD79a-, CD19-, cCD22- cCD79a-).
Epidemiology Only one case described, a 44-year-old-man (present report)
Cytology Undifferentiated blasts, without criteria specific for either lineage (myeloid or lymphoid)
Treatment The patient was treated according to the GRAALL-2014 protocol for adult acute lymphoblastic leukemia including induction, salvage course, then consolidation blocks and allo-HSCT transplantation.

Cytogenetics

Note No abnormality detected on conventional karyotype: 46,XY[20]
 
 
  FISH using a locus specific break-apart MECOM 3q26 probe (Metasystem XL D-5059-100-OG) confirmed the deletion at 3q26.2 locus telomeric to MECOM (loss of green signal).
Probes XL MECOM D-5059-100-OG

Genes involved and Proteins

Gene NameMECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplasic Syndrome 1 (MDS1/EVI1))
Location 3q26.2
Note MECOM is also known as EV1 or PRDM3. MECOM means MDS and EVI1 complex locus.
Dna / Rna EVI1 locus spans approximately 65 kb and contains 16 exons.
MDS1 locus spans approximately 500 kb and contains 4 exons.
The MDS1/EV1 transcript results from intergenic splicing of the second exon of MDS1 (telomere) to the second exon of EVI1 (centromere)
Protein MDS1/EVI1 protein contains a positive regulator domain (PR-domain) acting as a tumor-suppressor, a repression domain between two sets of several zinc finger motifs, and an acidic domain at its C-terminus. It is a nuclear transcriptional regulator involved in differentiation, proliferation and maintenance of hematopoietic stem cells.
Deregulation of the proto-oncogene MECOM by the 3q rearrangements (inv3 or t(3;3)) reposition a distal GATA2 enhancer, inducing an aberrant expression of EVI1 and conferring GATA2 fonctional haploinsufficiency (Gröschel et al, 2014). This mechanism is implicated in leukemogenesis of MDS/ AML with an extremely poor treatment outcome.
Gene NameTBL1XR1 (Transducin beta like 1 X-linked receptor 1)
Location 3q26.32
Note TBL1XR1 is also known as MRD41
Dna / Rna TBL1XR1 locus contains 18 exons. It is a member of the WD40 repeat-containing gene family
Protein The TBL1XR1 gene encodes a protein of 514 amino acids, which is a component of both N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) repressor complexes, which targeting nuclear receptor to repress transcription. TBL1XR1 is also required for transcriptional activation by many transcription factors (Li et al, 2015).
The protein contains a LisH domain (Lis1 homology domain) and a F-box like domain in its N-terminal region, and 8 WD40 repeats at the carboxy-terminus.
It seems to play a role in the maintenance of hematopoietic stem cells (Li et al, 2015).
TBL1XR1 mutations and rearrangements have been described in several lymphoid malignancies including diffuse large B cell lymphoma, acute lymphoblastic leukemia and acute promyelocytic leukemia (Heinen et al, 2016).

Result of the chromosomal anomaly

Hybrid gene
  Electrophoregram showing the fusion sequence of TBL1XR1/MECOM transcripts. The cDNA sequence analysis identified two in-frame transcripts, a major one which fused exon 9 of MECOM to exon 7 of TBL1XR1 and a minor one which fused exon 10 of MECOM to exon 7 of TBL1XR1.
 
Description 5'TBL1XR1-3'MECOM. TBL1XR1 exon 7 fused in-frame with MECOM exon 9 or 10.
Detection RT-PCR using MECOM and TBL1XR1 primers.
  
Fusion Protein
 
  Schematic representations of TBL1XR1 and MECOM proteins and TBL1XR1/MECOM putative fusion proteins.
Description The TBL1XR1/MECOM rearrangement may result in a putative hybrid protein containing the N-terminal portion (234 first aminoacids) of TBL1XR1 with its LisH, F-box and part of WD repeat domains and the C-terminal portion (381 last aminoacids) of MECOM retaining one set of zinc finger motif and the acidic domain.
  

To be noted

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

Four of the seven zinc fingers of the Evi-1 myeloid-transforming gene are required for sequence-specific binding to GA(C/T)AAGA(T/C)AAGATAA
Delwel R, Funabiki T, Kreider BL, Morishita K, Ihle JN
Mol Cell Biol. 1993 Jul;13(7):4291-300.
PMID 8321231
 
Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells.
Goyama S , Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, Chiba S, Kurokawa M.
Cell Stem Cell. 2008 Aug 7;3(2):207-20
PMID 18682242
 
A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.
Gröschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BA, Erpelinck C, van der Velden VH, Havermans M, Avellino R, van Lom K, Rombouts EJ, van Duin M, Döhner K, Beverloo HB, Bradner JE, Döhner H, Löwenberg B, Valk PJ, Bindels EM, de Laat W, Delwel R
Cell. 2014 Apr 10;157(2):369-381
PMID 24703711
 
A specific mutation in TBL1XR1 causes Pierpont syndrome.
Heinen CA, Jongejan A, Watson PJ, Redeker B, Boelen A, Boudzovitch-Surovtseva O, Forzano F, Hordijk R, Kelley R, Olney AH, Pierpont ME, Schaefer GB, Stewart F, van Trotsenburg AS, Fliers E, Schwabe JW, Hennekam RC.
J Med Genet 2016 May;53(5):330-7.
PMID 26769062
 
TBL1XR1 in physiological and pathological states.
Li JY, Daniels G, Wang J, Zhang X.
Am J Clin Exp Urol 2015 Apr 25;3(1):13-23. eCollection 2015.
PMID 26069883
 
The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells.
Maicas M, Vázquez I, Alis R, Marcotegui N, Urquiza L , Cortés-Lavaud X , Cristóbal I ,Garcèa-Sánchez MA, D. Odero MD
Biochim Biophys Acta. 2017 Jun;1860(6):721-729
PMID 28391050
 
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions.
Wieser R.
Gene 2007 Jul 15;396(2):346-57. Epub 2007 Apr 20.
PMID 17507183
 

Citation

This paper should be referenced as such :
Abdo C, Passet M, Maarek O, Clappier E
TBL1XR1/MECOM fusion; del(3)(q26.2q26.3) TBL1XR1/MECOM;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/del3q26TBL1XR1-MECOMID1823.html


Translocations implicated (Data extracted from papers in the Atlas)

 del(3)(q26.2q26.3) TBL1XR1/MECOM

External links

Mitelman databasedel(3)(q26.2q26.3) [Case List]    del(3)(q26.2q26.3) [Transloc-MCList] TBL1XR1/MECOM [Fusion-MCList]
arrayMap (UZH-SIB Zurich)Morph ( 9801/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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