Download Leukaemia Section del(11)(q23q23) MLL/CBL t(11;11)(q23;q23) MLL/CBL Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Short Communication
del(11)(q23q23) MLL/CBL
t(11;11)(q23;q23) MLL/CBL
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: October 2012
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del11q23q23ID1412.html
DOI: 10.4267/2042/48496
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
Protein
A major transcript of 14982 bp produces a 3969
amino acids protein from 36 of the 37 exons.
Contains from N-term to C-term a binding site for
MEN1, 3 AT hooks (binds to the minor grove of
DNA); 2 speckled nuclear localisation signals; 2
repression domains RD1 and RD2: RD1 or CXXC:
cystein methyl transferase, binds CpG rich DNA, has
a transcriptional repression activity; RD2 recruits
histone desacetylases HDAC1 and HDAC2; 3 plant
homeodomains (cystein rich zinc finger domains,
with homodimerization properties), 1 bromodomain
(may bind acetylated histones), and 1 plant
homeodomain; these domains may be involved in
protein-protein interaction; a FYRN and a FRYC
domain; a transactivation domain which binds CBP;
may acetylates H3 and H4 in the HOX area; a SET
domain: methyltransferase; methylates H3, including
histones in the HOX area for allowing chromatin to
be open to transcription. MLL is cleaved by taspase 1
into 2 proteins before entering the nucleus: a
p300/320 N-term protein called MLL-N, and a p180
C-term protein, called MLL-C. The FYRN and a
FRYC domains of native MLL associate MLL-N and
MLL-C in a stable complex; they form a multiprotein
complex with transcription factor TFIID.
General transcription factor; maintains HOX genes
expression in undifferentiated cells. Major regulator
of hematopoiesis and embryonic development; role in
cell cycle regulation.
Clinics and pathology
Disease
M1 acute myeloid leukemia
Epidemiology
Only one case to date, a 29-year-old female patient
(Fu et al., 2003; also reported in Shih et al., 2006).
Evolution
The patient achieved complete remission (CR) with
chemotherapy and remained in CR for 25 months.
Cytogenetics
Cytogenetics morphological
Cryptic translocation, missed by cytogenetic analysis.
The karyoptype showed a trisomy 22 and 3 marker
chromosomes.
Genes involved and
proteins
MLL starts at 118307.205 from pter, and CBL at
119076.986; they are normally separated by 29
known genes, which were apparently deleted in the
case under study.
MLL
Location
11q23.3
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(2)
126
del(11)(q23q23) MLL/CBL
Huret JL
CBL
Germinal mutations
Mutations located in the RING finger domain or the
linker region were found in a syndrome with clinical
features overlapping Noonan syndrome (Martinelli et
al., 2010).
Somatic mutations
CBL
mutations
have
been
found
in
myeloproliferative/myelodysplastic
syndromes,
causing the loss of its E3-ubiquitin ligase activity,
and an increase in cell proliferation (Aranaz et al.,
2012).
Location
11q23.3
Protein
Characterized by an N-terminal phosphotyrosine
kinase-binding domain involved in protein-protein
interaction, a short linker region, a zinc-binding
RING-finger domain mediating the E3 ubiquitin
ligase activity, proline-rich regions which mediate
interactions with SH3-domain-containing proteins,
and a C-terminal UBA (ubiquitin-associated) domain
which enables homodimer formation, and also
interacts with ubiquitin.
CBL is a member of the family of E3 ubiquitin
ligases (CBL, CBLB and CBLC) that negatively
regulates many signaling pathways downstream of
membrane receptor tyrosine kinases, and also some
non-receptor tyrosine-protein kinase (e.g. HCK).
CBL is an adaptor protein. CBL forms the "CBL
interactome" with associated proteins such as
ubiquitin,
SH3KBP1/CIN85,
ARHGEF7/COOL1/PIXB,
PDCD6IP/ALIX/AIP1,
and TSG101.
CBL is a regulator of cell growth, through the
regulation of pathways such as PI3K/AKT/MTOR
and RAS/RAF/MAPK. Acts as a tumor-suppressor
gene (reviews in Thien and Langdon, 2005; Dikic and
Schmidt, 2007).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(2)
Result of the chromosomal
anomaly
Hybrid gene
Description
5'MLL-3'CBL; breakpoint in exon 9 of MLL and
exon 8 of CBL.
Fusion protein
Description
Joins amino acid (aa) 1362 from MLL to aa 477 from
CBL. The fusion protein is made of 1791 aa (1362
from MLL and 429 from CBL). It contains the AT
hooks, Pro-rich, and the Zn finger CXXC type
domains from MLL in N-term, and the Pro-rich and
UBA domains from CBL in C-term.
127
del(11)(q23q23) MLL/CBL
Huret JL
Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S,
Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F,
Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM,
Zampino G, van der Burgt I, Ferrero GB, Mazzanti L,
Screpanti I, Yntema HG, Nillesen WM, Savarirayan R,
Zenker M, Dallapiccola B, Gelb BD, Tartaglia M.
Heterozygous germline mutations in the CBL tumorsuppressor gene cause a Noonan syndrome-like phenotype.
Am J Hum Genet. 2010 Aug 13;87(2):250-7
References
Fu JF, Hsu JJ, Tang TC, Shih LY. Identification of CBL, a
proto-oncogene at 11q23.3, as a novel MLL fusion partner in
a patient with de novo acute myeloid leukemia. Genes
Chromosomes Cancer. 2003 Jun;37(2):214-9
Thien CB, Langdon WY. c-Cbl and Cbl-b ubiquitin ligases:
substrate diversity and the negative regulation of signalling
responses. Biochem J. 2005 Oct 15;391(Pt 2):153-66
Aranaz P, Hurtado C, Erquiaga I, Miguéliz I, Ormazábal C,
Cristobal I, García-Delgado M, Novo FJ, Vizmanos JL. CBL
mutations in myeloproliferative neoplasms are also found in
the gene's proline-rich domain and in patients with the
V617FJAK2. Haematologica. 2012 Aug;97(8):1234-41
Shih LY, Liang DC, Fu JF, Wu JH, Wang PN, Lin TL, Dunn
P, Kuo MC, Tang TC, Lin TH, Lai CL. Characterization of
fusion partner genes in 114 patients with de novo acute
myeloid leukemia and MLL rearrangement. Leukemia. 2006
Feb;20(2):218-23
This article should be referenced as such:
Dikic I, Schmidt MH. Malfunctions within the Cbl interactome
uncouple receptor tyrosine kinases from destructive
transport. Eur J Cell Biol. 2007 Sep;86(9):505-12
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(2)
Huret JL. del(11)(q23q23) MLL/CBL. Atlas Genet Cytogenet
Oncol Haematol. 2013; 17(2):126-128.
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