Download Leukaemia Section t(10;16)(q22;p13) Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Mini Review
t(10;16)(q22;p13)
José Luis Vizmanos
Departamento de Genética, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain
Published in Atlas Database: May 2006
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1016q22p13ID1332.html
DOI: 10.4267/2042/38359
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology
47,XX,der(7)t(7;10)(p13;p11),+8,der(10)t(7;10)(p13;p
11)t(10;16)(q22;p13),der(16)t(10;16)(q22;p13)/46,XX.
Later it was also described in an 84-year-old male
without erythrophagocytosis and with this sole
cytogenetic aberration. In addition, a variant breakpoint
was described in a 52-year-old japanese woman with a
therapy-related myelodysplastic syndrome (t-MDS) and
also this sole translocation. Finally, another fusion
variant was described in an AML-M4 female patient
with the t(10;16) (q22;p13) and a t(11;17)(q23;q21).
Variants
There are no cytogenetic variants described, but there
are molecular variants due to different breakpoints in
the genes fused (see below).
Identity
G-band
analysis.
Partial
karyotype
showing
t(10;16)(q22;p13). Arrows indicate breakpoints in
chromosomes.
the
both
Clinics and pathology
Genes involved and Proteins
Disease
MYST4
Acute myeloid leukaemia (AML) M4/M5a and
therapy-related myelodysplastic syndromes (MDS).
Location: 10q22.2
Note: This gene is also involved in rearrangements
observed in uterine leiomyomata.
DNA / RNA
18 exons spanning 206.0 Kb. Transcription is from
centromere to telomere. Up to 7 alternative transcripts.
Protein
Histone acetyltransferase MYST4 is located probably
in the nucleous. And it is probably involved in both
positive (N-terminus) and negative (C-terminus)
regulation of transcription, maybe involved in cerebral
cortex development, required for RUNX2-dependent
transcriptional activation and ubiquitously expressed in
adult human tissues.
Epidemiology
Very rare, only four cases described.
Clinics
There is no erythrophagocytosis associated
Treatment
Bad response to chemotherapy.
Prognosis
Poor.
Cytogenetics
Additional anomalies
First described in a 4-year-old girl with AML M5a with
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
267
t(10;16)(q22;p13)
Vizmanos JL
Fig2. FISH analysis. FISH using BACs RPCI-11 461A8 (green) and RPCI-11 95J11 (red) showing that the signal of 95J11, which covers
the initial part of the CREBBP gene, is split between der(10) and der(16).
cell differentiation, apoptosis, and proliferation and it is
involved in the regulation of cell cycle during G1/S
transition.
CREBBP
Location: 16p13.3
Note: This gene is also involved in t(8;16)(p11;p13)
with MYST3. CREBBP fusion observed in M4 ANLL
and therapy related AML; t(11;16)(q23;p13) with MLL
CREBBP fusion observed also in therapy related.
Mutations of CREBBP are associated with RubinsteinTaybi syndrome.
DNA / RNA
Up to 32 exons spanning 154,14 Kb. Transcription is
from centromere to telomere and up to 3 alternative
transcripts between 8,0 and 8,7 Kb.
Protein
CREBBP is a wide expression histone acetyltransferase
enzyme which locates in the nucleous. Function binds
specifically to the DNA-binding protein CREB
connecting it to the basal transcriptional machinery.
Also acetylates non-histone proteins, like NCOA3
coactivator. It has an essential role in embryogenesis,
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
Results of the chromosomal
anomaly
Hybrid gene
Description
Fusion in-frame between MYST4 exon 17 and
CREBBP exon 3. Variants fusing MYST4 exon 16 and
CREBBP exon 5; MYST4 exon 17 and CREBBP exon
7 have also been described.
Transcript
5' MYST4 - CREBBP 3'
Detection protocole
CREBBP-MYST4 has been also detected.
268
t(10;16)(q22;p13)
Vizmanos JL
Schematic representation of the fusion MYST4-CREBBP consequence of the t(10;16)(q22;p13). From up to down: MYST4 and
CREBBP structures. H15 domain: domain in histone families 1 and 5; PHD zinc fingers: plant homeodomain (PHD) with a C4HC3-type
motif, this domain is widely distributed in eukaryotes and it has been found in many chromatin regulatory factors; MOZ_SAS family
region: this region has been suggested to be homologous to acetyltransferases but this similarity is not supported by sequence analysis;
KIX domain: bind domain for CBP and P300, this domain also binds to transactivation domains of other nuclear factors including Myb
and Jun.
Fusion protein
References
Description
In all cases published to date the breakpoints occur in
the acidic domain of MYST4 but at different locations
of the CREBBP protein: in the nuclear receptor-binding
domain, in a C/H rich domain or between this domain
and the KIX domain. The putative MYST4-CBP
chimaeric protein retains the part of MYST4 that
encodes the zinc fingers, two nuclear localization
signals (NLS1 and NLS2), the HAT domain, and a
portion of the acidic domain, and most of the CBP
protein, including its HAT domain.
Oncogenesis
MYST4 has a 60% identity and 66% similarity to
MYST3. All the fusions involving this genes result in
several fusion proteins that target the acidic domain of
MYST3 and MYST4. The partner fusion partners share
also functional regions. All the fusion proteins are
suspected to be leukaemogenic as a consequence of
aberrant histone acetylation and transcription
regulation, due probably but not exclusively, to the
concomitant presence of two HAT domains coming
from the different partners.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U,
Billström R, Strömbeck B, Mitelman F, Johansson B. Fusion of
the MORF and CBP genes in acute myeloid leukemia with the
t(10;16)(q22;p13). Hum Mol Genet 2001;10:395-404.
Kojima K, Kaneda K, Yoshida C, Dansako H, Fujii N, Yano T,
Shinagawa K, Yasukawa M, Fujita S, Tanimoto M. A novel
fusion variant of the MORF and CBP genes detected in
therapy-related
myelodysplastic
syndrome
with
t(10;16)(q22;p13). Br J Haematol 2003;120:271-273.
Vizmanos JL, Larráyoz MJ, Lahortiga I, Floristán F, Alvarez C,
Odero MD, Novo FJ, Calasanz MJ. t(10;16)(q22;p13) and
MORF-CREBBP fusion is a recurrent event in acute myeloid
leukaemia. Genes Chromosomes Cancer 2003;36:402-405.
Murati A, Adélaïde J, Mozziconacci MJ, Popovici C, Carbuccia
N, Letessier A, Birg F, Birnbaum D, Chaffanet M. Variant
MYST4-CBP gene fusion in a t(10;16) acute myeloid
leukaemia. Br J Haematol 2004;125:601-604.
This article should be referenced as such:
Vizmanos JL. t(10;16)(q22;p13). Atlas Genet Cytogenet Oncol
Haematol.2006;10(4):267-269.
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