Download Leukaemia Section t(12;12)(p13;q13) ETV6/BAZ2A Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
t(12;12)(p13;q13) ETV6/BAZ2A
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: March 2013
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1212p13q13ID1452.html
DOI: 10.4267/2042/51429
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Cytogenetics
Disease
Cytogenetics morphological
Acute leukemias
In the case where ETV6/BAZ2A rearrangement was
ascertained, the rearrangement between 12p13 and
12q13 was cryptic (Panagopoulos et al., 2006). The
other ALL case also had a trisomy 16 and a trisomy 21.
The t(12;12)(p13;q13) was an additional anomaly to a
t(11;19)(q23;p13.1) in the treatment related AML-M2
case.
The apparently de novo AML-M2 case have had a
del(7q) prior to the t(12;12).
The M6-AML case had a del(5q), a del(20q) and a
complex karyotype.
Clinics
Out of 5 cases herein taken into account, 3 cases
presented with a rearranged ETV6 gene, and only one
of these cases was identified to carry an ETV6/BAZ2A
hybrid gene. This case was a 3-year-old girl with a preB acute lymphoblastic leukaemia (CD10+ ALL). She
achieved complete remission (CR), and was remaining
in CR 18 months after diagnosis (Panagopoulos et al.,
2006).
The 2 other ETV6+ cases were acute myeloid leukemia
(AML) cases: a 77-year-old male patient with AMLM2. Complete remission was achieved; he relapsed and
died of sepsis (Saitoh et al., 2002); and a 46-year-old
female patient with treatment related AML-M2,
developping years after treatment for breast cancer; the
patient has been in continuous relapse for the last 4
months after onset of AML (Manola et al., 2008).
The 2 last cases were: a 4-years-old boy with ALL; the
patient was alive 27 months after diagnosis (Heerema
et al., 1985); and a 62-years-old female patient with
AML-M6 with a 2 months survival (Mazzella et al.,
1998).
Altogether, this makes 2 pediatric ALL cases, and 3
adult AML cases, with perhaps different prognoses
between the two categories. Excluded here is a case of
refractory anemia with excess blasts with HMGA2
involvement (Odero et al., 2005), although the 4 above
mentionned cases where BAZ2A was not studied may
also have had a HMGA2 rearrangement.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9)
Genes involved and proteins
ETV6
Location
12p13.2
Protein
ETV6 is a transcriptional repressor belonging to the
ETS family. ETV6 displays a HLH domain (also
referred to as the pointed (PNT) or sterile alpha motif
(SAM) domain), responsible for hetero- and
homodimerization, a central domain involved in the
recruitment of a repression complex including NCOR2
and SIN3, and an ETS domain, responsible for
sequence specific DNA-binding to DNA-responsive
elements.
Repression involves the recruitment of co-repressor
complexes and HDACs or the recruitment of
L3MBTL-containing polycomb group-complexes that
facilitate repression by chromatin remodeling. ETV6
640
t(12;12)(p13;q13) ETV6/BAZ2A
Huret JL
binds to nuclear receptors RARA and RXRA and
represses gene activation. ETV6 is as a selective and
essential regulator of stem cells, important in vitelline
angiogenesis and in bone marrow hematopoiesis. ETV6
expands erythroid precursors and stimulates
hemoglobin synthesis (Knezevich, 2005; EguchiIshimae et al., 2009; Meester-Smoor et al., 2011).
References
Heerema NA, Palmer CG, Baehner RL. Karyotypic and clinical
findings in a consecutive series of children with acute
lymphocytic leukemia. Cancer Genet Cytogenet. 1985
Jun;17(2):165-79
Mazzella FM, Kowal-Vern A, Shrit MA, Wibowo AL, Rector JT,
Cotelingam JD, Collier J, Mikhael A, Cualing H, Schumacher
HR. Acute erythroleukemia: evaluation of 48 cases with
reference to classification, cell proliferation, cytogenetics, and
prognosis. Am J Clin Pathol. 1998 Nov;110(5):590-8
BAZ2A
Location
12q13.3
Protein
BAZ2A comprises from N-term to C-term a MBD
(methyl-CpG-binding) domain, 2 AT hooks, a DDT
(DNA binding homeobox and different transcription
factors), 2 AT hooks again, a PHD-type zinc finger,
and a bromo domain. The bromo domain and the PHDtype zinc finger recognize and bind histone H4. These 2
domains play a central role in the recruitment of
chromatin silencing proteins such as DNMT1,
DNMT3B and HDAC1 (Swiss-Prot). The NoRC
(nucleolar remodeling complex) comprises BAZ2A and
SMARCA5. A mechanism for silencing active
ribosomal RNA (rRNA) genes is the recruitment by
TTF1 (transcription termination factor-1) of NoRC to
the promoter of rRNAs in the nucleolus. PARP1,
component of the machinery that establishes and
maintains silent rDNA chromatin during cell division,
binds to BAZ2A (Guetg et al., 2012). BAZ2A is upregulated in patients with chronic lymphocytic
leukemia (Hanlon et al., 2009).
Saitoh T, Nakamura T, Inoue M, Hatta Y, Yamazaki T,
Takeuchi J, Sawada U, Horie T. Different clones of
t(1;12)/t(12;12) involving the ETV6 gene in a case of acute
myeloid leukemia. Cancer Genet Cytogenet. 2002
Sep;137(2):138-41
Odero MD, Grand FH, Iqbal S, Ross F, Roman JP, Vizmanos
JL, Andrieux J, Laï JL, Calasanz MJ, Cross NC. Disruption and
aberrant expression of HMGA2 as a consequence of diverse
chromosomal translocations in myeloid malignancies.
Leukemia. 2005 Feb;19(2):245-52
Knezevich S.. ETV6 (ETS variant gene 6 (TEL oncogene)).
Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL:
http://AtlasGeneticsOncology.org/Genes/ETV6ID38.html
Panagopoulos I, Strombeck B, Isaksson M, Heldrup J,
Olofsson T, Johansson B.. Fusion of ETV6 with an intronic
sequence of the BAZ2A gene in a paediatric pre-B acute
lymphoblastic leukaemia with a cryptic chromosome 12
rearrangement. Br J Haematol. 2006 May;133(3):270-5.
Manola KN, Georgakakos VN, Margaritis D, Stavropoulou C,
Panos C, Kotsianidis I, Pantelias GE, Sambani C.. Disruption
of the ETV6 gene as a consequence of a rare translocation
(12;12)(p13;q13) in treatment-induced acute myeloid leukemia
after breast cancer. Cancer Genet Cytogenet. 2008 Jan
1;180(1):37-42.
Result of the chromosomal
anomaly
Eguchi-Ishimae M, Eguchi M, Maki K, Porcher C, Shimizu R,
Yamamoto M, Mitani K.. Leukemia-related transcription factor
TEL/ETV6 expands erythroid precursors and stimulates
hemoglobin synthesis. Cancer Sci. 2009 Apr;100(4):689-97.
doi: 10.1111/j.1349-7006.2009.01097.x. Epub 2009 Mar 11.
Hybrid gene
Transcript
Transcript consisting of exons 1 and 2 of ETV6 and a
sequence from intron 1 of BAZ2A. This transcript is
not expected to produce any chimeric protein.
Hanlon K, Rudin CE, Harries LW.. Investigating the targets of
MIR-15a and MIR-16-1 in patients with chronic lymphocytic
leukemia (CLL). PLoS One. 2009 Sep 25;4(9):e7169. doi:
10.1371/journal.pone.0007169.
Meester-Smoor MA, Janssen MJ, ter Haar WM, van Wely KH,
Aarnoudse AJ, van Oord G, van Tilburg GB, Zwarthoff EC..
The ETS family member TEL binds to nuclear receptors RAR
and RXR and represses gene activation. PLoS One.
2011;6(9):e23620. doi: 10.1371/journal.pone.0023620. Epub
2011 Sep 16.
Fusion protein
Description
The transcript may encode a truncated form of ETV6,
containing the first 54 amino acids (aa) of ETV6,
followed by 16 aa from the 3' fusion sequence.
Oncogenesis
The production of a truncated form of ETV6 is
reminiscent of ETV6 fusions with MDS2, FCHO2,
PER1, and STL, according to Panagopoulos et al.,
2006. BAZ2A may also be deregulated.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(9)
Guetg C, Scheifele F, Rosenthal F, Hottiger MO, Santoro R..
Inheritance of silent rDNA chromatin is mediated by PARP1 via
noncoding RNA. Mol Cell. 2012 Mar 30;45(6):790-800. doi:
10.1016/j.molcel.2012.01.024. Epub 2012 Mar 8.
This article should be referenced as such:
Huret JL. t(12;12)(p13;q13) ETV6/BAZ2A. Atlas
Cytogenet Oncol Haematol. 2013; 17(9):640-641.
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