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t(12;18)(p13;q12) ETV6/SETBP1

Written2012-03Ion Cristóbal, Laura Garcia-Orti, Paula Aranaz, María J Calasanz, Maria D Odero
Division of Oncology, CIMA, University of Navarra, E-31008 Pamplona, Spain (IC, LGO, MDO); Department of Genetics, School of Sciences, University of Navarra, E-31008 Pamplona, Spain (IC, PA, MJC, MDO)

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ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1580
Note The balanced translocation between the short arm of chromosome 12 and the long arm of the chromosome 18 -t(12;18)(p13;q12)- has been described in a patient with acute myeloid leukemia secondary to myelodysplastic syndrome. The key event in the t(12;18)(p13;q12) involving ETV6 is the overexpression of SETBP1 (18q12), a gene located close to the breakpoint (Cristobal et al., 2010).
  Partial karyotype of a patient with AML-M5 and a t(12;18)(p13;q12). Derivative chromosomes are indicated by arrows.

Clinics and Pathology

Disease Acute Myeloid Leukemia (AML-M5) secondary to Myelodysplastic Syndrome (MDS).
Epidemiology This is a rare chromosomal rearrangement, characterized at molecular level in only one AML patient to date.
Clinics A 76-year-old caucasian man was diagnosed with myelodysplastic syndrome (MDS). Disease evaluation of the patient 3 years after the diagnosis showed anorexia, perspiration and loss of 7 kg.
Cytology Blast morphology was indicative of acute monocytic leukemia.
Pathology Bone marrow aspirate was hypercellular, showing 80% blasts.
Treatment The patient received standard induction chemotherapy for two months, and had partial remission at the next evaluation.
Evolution The patient relapsed 2 months later and, eventually, died.
Prognosis SETBP1 overexpression is a marker of poor prognosis in AML, with special relevance in the subgroup of elderly patients (Cristobal et al., 2010).


The t(12;18)(p13;q12) involves the ETV6 gene (12p13), a transcription factor frequently rearranged in both myeloid and lymphoid leukemias. More than 15 ETV6 fusion gene partners have been described. Most translocations involving ETV6 generate fusion genes that lead to the activation of either unrelated transcription factors or kinases (Cools et al., 2002). However, in some cases functionally significant fusions could not be identified and an alternative mechanism consisting in the ectopic expression of genes located close to the breakpoints has been described. This molecular mechanism, which has been described mainly in lymphoid leukemias and lymphomas, is an uncommon mechanism in myeloid leukemias, although some examples have been reported (Cools et al., 2002; Odero et al., 2002; Nucifora et al., 2006). The key event in the t(12;18)(p13;q12) involving ETV6 is the overexpression of SETBP1 (18q12), a gene located close to the breakpoint (Cristobal et al., 2010).


Cytogenetics Morphological t(12;18)(p13;q12) as the sole abnormality; +19 as an additional anomaly at relapse.
Cytogenetics Molecular FISH showed that the breakpoint on 12p13 was located between exons 2 and 3 of ETV6. To confirm the position of the breakpoint on chromosome 18, BACs located at 18q12 were used as probes in FISH experiments. Analysis on BM cells of the patient showed that one signal hybridized to the normal chromosome 18, and the other split and hybridized to both der(18) and der(12). FISH showed that the breakpoint was located 5' and close to the SETBP1 gene.
  FISH analysis indicating the breakpoint on 18q12: probe RP11-252G8 (green) splits and hybridizes in both der(18) and der(12).
Probes The order of the probes on 18q12 is centromere-840B16-937P23-252G8-941F5-telomere. To map the breakpoints bacterial artificial chromosomes obtained from the Roswell Park Cancer Institute (Buffalo, NY) were used and labeled with SpectrumGreen-dUTP or SpectrumOrange-dUTP.
Additional anomalies The presence of a trisomy 19 in one clone suggests that SETBP1 overexpression, as a consequence of position effects, could cooperate with other additional aberrations to the development of AML in this patient.

Genes involved and Proteins

Note The key event in the t(12;18)(p13;q12) involving ETV6 is the overexpression of SETBP1 (18q12), a gene located close to the breakpoint (Cristobal et al., 2010).
Gene Name ETV6
Location 12p13
Protein The ETV6 gene encodes a transcription factor frequently rearranged in both myeloid and lymphoid leukemias. Translocations involving this gene mostly result in the generation of in-frame fusion genes between different domains of ETV6 and partner genes encoding either kinases or transcription factors with importance in cancer. However, in some cases functionally significant fusions could not be detected, and the deregulation of the expression of oncogenes located close to the breakpoints has been described as an alternative leukemogenic mechanism (Cools et al., 2002).
Gene Name SETBP1
Location 18q12
Protein The SETBP1 gene encodes a protein of 1542 amino acids and a molecular weight of 170 kDa, with a predominantly nuclear location (Minakuchi et al., 2001; Cristobal et al., 2010). The protein contains a region homologous to the dimerization domain of SKI, and a SET-binding region (Minakuchi et al., 2001). The protein SET (I2PP2A/TAF-Iβ) inhibits PP2A, a phosphatase with a pivotal role in cancer as a tumor supressor (Mumby, 2007), through the phosphorylation of the PP2Ac tyrosine-307 (Li et al., 1996). Interestingly, activation of SETBP1 expression by retroviral integration in hematopoietic progenitor cells has been reported to confer a growth advantage leading to clonal expansion (Ott et al., 2006). Moreover, it has been reported that SETBP1 overexpression protects SET from protease cleavage, increasing the amount of full-length SET protein, and leading to the formation of a SETBP1-SET-PP2A complex that results in PP2A inhibition, and therefore promotes the proliferation and expansion of leukemic cells (Cristobal et al., 2010).

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.


Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13).
Cools J, Mentens N, Odero MD, Peeters P, Wlodarska I, Delforge M, Hagemeijer A, Marynen P.
Blood. 2002 Mar 1;99(5):1776-84.
PMID 11861295
SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia.
Cristobal I, Blanco FJ, Garcia-Orti L, Marcotegui N, Vicente C, Rifon J, Novo FJ, Bandres E, Calasanz MJ, Bernabeu C, Odero MD.
Blood. 2010 Jan 21;115(3):615-25. Epub 2009 Nov 16.
PMID 19965692
The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A.
Li M, Makkinje A, Damuni Z.
J Biol Chem. 1996 May 10;271(19):11059-62.
PMID 8626647
Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET.
Minakuchi M, Kakazu N, Gorrin-Rivas MJ, Abe T, Copeland TD, Ueda K, Adachi Y.
Eur J Biochem. 2001 Mar;268(5):1340-51.
PMID 11231286
PP2A: unveiling a reluctant tumor suppressor.
Mumby M.
Cell. 2007 Jul 13;130(1):21-4. (REVIEW)
PMID 17632053
EVI1 and hematopoietic disorders: history and perspectives.
Nucifora G, Laricchia-Robbio L, Senyuk V.
Gene. 2006 Mar 1;368:1-11. Epub 2005 Nov 28. (REVIEW)
PMID 16314052
A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13) in a patient with myelodysplastic syndrome.
Odero MD, Vizmanos JL, Roman JP, Lahortiga I, Panizo C, Calasanz MJ, Zeleznik-Le NJ, Rowley JD, Novo FJ.
Genes Chromosomes Cancer. 2002 Sep;35(1):11-9.
PMID 12203785


This paper should be referenced as such :
Cristòbal, I ; Garcia-Orti, L ; Aranaz, P ; Calasanz, MJ ; Odero, MD
Atlas Genet Cytogenet Oncol Haematol. 2012;16(8):582-584.
Free journal version : [ pdf ]   [ DOI ]
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Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes SETBP1

Translocations implicated (Data extracted from papers in the Atlas)

 t(12;18)(p13;q12) ETV6/SETBP1

External links

Mitelman databaset(12;18)(p13;q12) [Case List]    t(12;18)(p13;q12) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9989/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
Disease databaset(12;18)(p13;q12) ETV6/SETBP1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

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