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t(1;12)(p36;p13) ETV6/PRDM16

Written2016-08Francois P. Duhoux, Hélène A. Poirel
Cliniques universitaires Saint-Luc, Université catholique de Louvain / helene.antoine-poirel@uclouvain.be

Abstract Review on t(1;12)(p36;p13) translocations, with data on clinics, and the genes involved.

Keywords chromosome 1; chromosome 12; t(1;12)(p36;p13); PRDM16; ETV6

(Note : for Links provided by Atlas : click)

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 1697

Clinics and Pathology

Disease Acute myeloid leukaemia (AML).
Phenotype / cell stem origin AML M4 according to immunophenotyping vs M1 according to cytology.
Epidemiology Found in one case of AML in a 46 years old female Duhoux et al., 2012).
Clinics (
Cytology Leukemic infiltrate of myeloid origin (blasts I and II); high proportion of myeloid blast cells and restricted percentage of monocytes.
Prognosis The patient died 12 months after diagnosis.

Cytogenetics

Cytogenetics Morphological The t(1;12)(p36;p13.2) was the sole anomaly.
 
 
  Left: FISH using the LSI® ETV6 probe : the probe is split between the der(1) and the der(12. Right: FISH using specific probes for PRDM16 (RP5-907A6 and RP1-163G9): the RP1-163G9 probe is split between the der(1) and the der(12), the RP5-907A6 probe is translocated to the der(12)PROBES RP5-907A6 (FITC), RP1-163G9 (Cy3) and LSI® ETV6

Genes involved and Proteins

Gene NamePRDM16 (PR domain containing 16)
Location 1p36.32
Dna / Rna 11 splice variants
Protein 1276 amino acids and smaller proteins. Contains a N-term PR domain; 7 Zinc fingers, a proline-rich domain, and 3 Zinc fingers in the C-term. Binds DNA. Transcription activator; PRDM16 has an intrinsic histone methyltransferase activity. PRDM16 forms a transcriptional complex with CEBPB. PRDM16 plays a downstream regulatory role in mediating TGFB signaling (Bjork et al., 2010). PRDM16 induces brown fat determination and differentiation. PRDM16 is expressed selectively in the earliest stem and progenitor hematopoietic cells, and is required for the maintenance of the hematopoietic stem cell pool during development. PRDM16 is also required for survival, cell-cycle regulation and self-renewal in neural stem cells (Chuikov et al., 2010; Kajimura et al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).
Gene NameETV6 (ets variant 6)
Location 12p13.2
Protein 452 amino acids. The ETV6 protein contains from N-term to C-Term a HLH (helix-loop-helix, aa 40-124) domain (also referred to as the pointed or sterile alpha motif domain), responsible for hetero- and homodimerization, an internal domain, involved in the recruitment of a repression complex including NCOR1 (17p12), NCOR2 (12q24.31), SIN3A (15q24.2), and SIN3B (19p13.11), and an ETS domain (aa 339-420), responsible for sequence specific DNA-binding and protein-protein interaction (De Braekeleer et al., 2014).

Result of the chromosomal anomaly

Hybrid gene
  Schematic representation of the putative ETV6-PRDM16 fusion protein, PRD = prolin-rich domain, DBD1 = DNA-binding domain 1, PRR = prolin-rich domain, RD = repressor domain, DBD2 = DNA-binding domain 2, AD = acidic domain.
 
Description ETV6 exon 4 is fused to PRDM16 exon 2.
Detection PCR, FISH.
  

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

Prdm16 is a physiologic regulator of hematopoietic stem cells.
Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW.
Blood. 2011 May 12;117(19):5057-66. doi: 10.1182/blood-2010-08-300145. Epub 2011 Feb 22.
PMID 21343612
 
Prdm16 is required for normal palatogenesis in mice.
Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR.
Hum Mol Genet. 2010 Mar 1;19(5):774-89. doi: 10.1093/hmg/ddp543. Epub 2009 Dec 11.
PMID 20007998
 
The Multifaceted Roles of PRDM16: Adipose Biology and Beyond.
Chi J, Cohen P.
Trends Endocrinol Metab. 2016 Jan;27(1):11-23. doi: 10.1016/j.tem.2015.11.005. Epub 2015 Dec 11. Review.
PMID 26688472
 
Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress.
Chuikov S, Levi BP, Smith ML, Morrison SJ.
Nat Cell Biol. 2010 Oct;12(10):999-1006. doi: 10.1038/ncb2101. Epub 2010 Sep 12.
PMID 20835244
 
ETV6 (ets variant 6).
De Braekeleer E, Douet-Guilbert N, De Braekeleer M.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(12):886-899.
 
PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies.
Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA; Groupe Francophone de Cytogénétique Hématologique (GFCH); Belgian Cytogenetic Group for Haematology and Oncology (BCG-HO).
Br J Haematol. 2012 Jan;156(1):76-88. doi: 10.1111/j.1365-2141.2011.08918.x. Epub 2011 Nov 3.
PMID 22050763
 
Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex.
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM.
Nature. 2009 Aug 27;460(7259):1154-8. Epub 2009 Jul 29.
PMID 19641492
 

Citation

This paper should be referenced as such :
Duhoux FP, Poirel HA
t(1;12)(p36;p13) ETV6/PRDM16;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0112p36p13ID1697.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(1;12)(p36;p13) ETV6/PRDM16

External links

Mitelman databaset(1;12)(p36;p13) [Case List]    t(1;12)(p36;p13) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaset(1;12)(p36;p13) ETV6/PRDM16
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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