Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS

Leukaemia Section Short Communication t(1;12)(p36;p13) ETV6/PRDM16 Francois P. Duhoux, Hélène A. Poirel Cliniques universitaires Saint-Luc, Université catholique de Louvain / helene.antoine- [email protected]

Published in Atlas Database: August 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0112p36p13ID1697.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68255/08-2016-t0112p36p13ID1697.pdf DOI: 10.4267/2042/68255 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Review on t(1;12)(p36;p13) translocations, with data on clinics, and the involved. Keywords 1; chromosome 12; t(1;12)(p36;p13); PRDM16; ETV6 Clinics and pathology Genes involved and Disease Acute myeloid leukaemia (AML). PRDM16 (PR domain containing 16) Phenotype/cell stem origin Location 1p36.32 AML M4 according to immunophenotyping vs M1 according to cytology. DNA/RNA Epidemiology 11 splice variants Found in one case of AML in a 46 years old female 1276 amino acids and smaller proteins. Contains a Duhoux et al., 2012). N-term PR domain; 7 Zinc fingers, a proline-rich Cytology domain, and 3 Zinc fingers in the C-term. Binds Leukemic infiltrate of myeloid origin (blasts I and DNA. Transcription activator; PRDM16 has an II); high proportion of myeloid blast cells and intrinsic histone methyltransferase activity. restricted percentage of monocytes. PRDM16 forms a transcriptional complex with CEBPB. PRDM16 plays a downstream regulatory Prognosis role in mediating TGFB signaling (Bjork et al., The patient died 12 months after diagnosis. 2010). PRDM16 induces brown fat determination and differentiation. PRDM16 is expressed Cytogenetics selectively in the earliest stem and progenitor hematopoietic cells, and is required for the Cytogenetics morphological maintenance of the hematopoietic stem cell pool The t(1;12)(p36;p13.2) was the sole anomaly. during development.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6) 215 t(1;12)(p36;p13) ETV6/PRDM16 Duhoux FP, Poirel HA

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

PRDM16 is also required for survival, cell-cycle including NCOR1 (17p12), NCOR2 (12q24.31), regulation and self-renewal in neural stem cells SIN3A (15q24.2), and SIN3B (19p13.11), and an (Chuikov et al., 2010; Kajimura et al., 2010; Aguilo ETS domain (aa 339-420), responsible for sequence et al., 2011; Chi and Cohen, 2016). specific DNA-binding and protein-protein ETV6 (ets variant 6) interaction (De Braekeleer et al., 2014). Location Result of the chromosomal 12p13.2 Protein anomaly 452 amino acids. The ETV6 protein contains from Hybrid N-term to C-Term a HLH (helix-loop-helix, aa 40- 124) domain (also referred to as the pointed or sterile Description alpha motif domain), responsible for hetero- and ETV6 exon 4 is fused to PRDM16 exon 2. homodimerization, an internal domain, involved in Detection the recruitment of a repression complex PCR, FISH.

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.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6) 216

t(1;12)(p36;p13) ETV6/PRDM16 Duhoux FP, Poirel HA

K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, References Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche- Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel physiologic regulator of hematopoietic stem cells. Blood. HA; Groupe Francophone de Cytogénétique 2011 May 12;117(19):5057-66 Hématologique (GFCH); Belgian Cytogenetic Group for Haematology and Oncology (BCG-HO).. PRDM16 (1p36) Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. translocations define a distinct entity of myeloid Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89 malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Chi J, Cohen P. The Multifaceted Roles of PRDM16: Jan;156(1):76-88. doi: 10.1111/j.1365-2141.2011.08918.x. Adipose Biology and Beyond. Trends Endocrinol Metab. Epub 2011 Nov 3. 2016 Jan;27(1):11-23 Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 Gygi SP, Spiegelman BM.. Initiation of myoblast to brown promotes stem cell maintenance in multiple tissues, partly fat switch by a PRDM16-C/EBP-beta transcriptional by regulating oxidative stress. Nat Cell Biol. 2010 complex. Nature. 2009 Aug 27;460(7259):1154-8. Epub Oct;12(10):999-1006 2009 Jul 29. De Braekeleer E, Douet-Guilbert N, De Braekeleer M.. This article should be referenced as such: ETV6 (ets variant 6). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(12):886-899. Duhoux FP, Poirel HA. t(1;12)(p36;p13) ETV6/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula 21(6):215-217.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(6) 217