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del(11)(q23q23) KMT2A/CBL

t(11;11)(q23;q23) KMT2A/CBL

Written2012-10Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9807/3 Mixed phenotype acute leukaemia with t(v;11q23); MLL rearranged
ICD-Morpho 9813/3 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1412

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

Note 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.
Gene Name KMT2A
Location 11q23.3
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.
Gene Name CBL
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).
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).

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.
  

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.

Bibliography

CBL mutations in myeloproliferative neoplasms are also found in the gene's proline-rich domain and in patients with the V617FJAK2.
Aranaz P, Hurtado C, Erquiaga I, Migueliz I, Ormazabal C, Cristobal I, Garcia-Delgado M, Novo FJ, Vizmanos JL.
Haematologica. 2012 Aug;97(8):1234-41. doi: 10.3324/haematol.2011.052605. Epub 2012 Feb 7.
PMID 22315494
 
Malfunctions within the Cbl interactome uncouple receptor tyrosine kinases from destructive transport.
Dikic I, Schmidt MH.
Eur J Cell Biol. 2007 Sep;86(9):505-12. Epub 2007 Jun 5. (REVIEW)
PMID 17553592
 
Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia.
Fu JF, Hsu JJ, Tang TC, Shih LY.
Genes Chromosomes Cancer. 2003 Jun;37(2):214-9.
PMID 12696071
 
Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.
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.
Am J Hum Genet. 2010 Aug 13;87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. Epub 2010 Jul 8.
PMID 20619386
 
Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement.
Shih LY, Liang DC, Fu JF, Wu JH, Wang PN, Lin TL, Dunn P, Kuo MC, Tang TC, Lin TH, Lai CL.
Leukemia. 2006 Feb;20(2):218-23.
PMID 16341046
 
c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses.
Thien CB, Langdon WY.
Biochem J. 2005 Oct 15;391(Pt 2):153-66. (REVIEW)
PMID 16212556
 

Citation

This paper should be referenced as such :
Huret, JL
del(11)(q23q23) MLL/CBL - t(11;11)(q23;q23) MLL/CBL
Atlas Genet Cytogenet Oncol Haematol. 2013;17(2):126-128.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/del11q23q23ID1412.html


Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 del(11)(q23q23) KMT2A/CBL
 t(11;11)(q23;q23) KMT2A/CBL

External links

KMT2A (11q23.3) CBL (11q23.3)

KMT2A (11q23.3) CBL (11q23.3)

Mitelman databasedel(11)(q23q23) [Case List]    del(11)(q23q23) [Association List] Mitelman database (CGAP - NCBI)
Mitelman databaset(11;11)(q23;q23) [Case List]    t(11;11)(q23;q23) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9807/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9813/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionKMT2A/CBL KMT2A (11q23.3) CBL (11q23.3)   [fusion1970]   [fusion1971]  
TICdbKMT2A/CBL  KMT2A (11q23.3) CBL (11q23.3)
 
Disease databasedel(11)(q23q23) KMT2A/CBL
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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