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t(11;11)(q14;q23) KMT2A/PICALM

inv(11)(q14q23) KMT2A/PICALM

Written2017-03Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France. jean-loup.huret@chu-poitiers.fr

Abstract Review on t(11;11)(q14;q23) and inv(11)(q14q23) KMT2A/PICALM, with data on clinics and the genes involved.

Keywords Chromosome 11; KMT2A; PICALM; acute myeloid leukemia; acute lymphoblastic leukemia.

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9891/3 Acute monoblastic and monocytic leukaemia
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
Atlas_Id 1411

Clinics and Pathology

Disease Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
Embryonic origin
Clinics There was the case of a 12-week-old female infant with acute monocytic leukemia (M5b) and inv(11)(q14q23), dead at day 11 (Wechsler et al., 2003).
Otherwise, in a large study of cases of chromosomal rearrangements involving the human KMT2A (MLL) gene, a t(11;11)(q14;q23) or inv(11)(q14q23) KMT2A/PICALM was found in 1 out of 440 infant ALL patients, 1 out of 105 infant AML patients, 1 out of 205 pediatric ALL patients, 1 out of 272 adult AML patients, and none in 202 pediatric AML patients, nor in 333 adult ALL patients (Meyer et al., 2013). Note: the case by Meyer et al., 2006 was reused in Meyer et al., 2013.

Genes involved and Proteins

Gene Name PICALM
Location 11q14.2
 
Dna / Rna 24 transcripts
Protein PICALM codes for a 652-aa protein, and shorter isoforms. It is an endocytosis adaptor, in the initial stages of coated pit invagination together with clathrin, AP2 (adaptor related protein complex subunits) and PtdIns(4,5)P2 (phosphatidylinositol-4,5- bisphosphate) containing membranes. PICALM interacts with CLTC (clathrin heavy chain) promoting assembly of clathrin triskelia into clathrin cages. Clathrin is the major binding partner of PICALM (Archangelo et al., 2006). PICALM is required for erythroid maturation and transferrin internalization.
PICALM domains: PICALM contains an AP180 N-terminal homology (ANTH) domain (or ENTH domain for epsin NH2-terminal domain)) (note: "AP180" is SNAP91, and epsin is EPN1, EPN2 or EPN3) and an assembly domain (AD). ANTH: amino acids (aa) 1-289; AD: aa 290-652.
ANTH: The ANTH domain is folded; it binds phosphatidylinositol-4,5- bisphosphate (PtdIns(4,5)P2) via a lysine-rich motif, and vesicle associated membrane proteins (VAMPs). There are nine alpha helices forming a solenoid (aa 20-30, 40-50, 56-67, 71-90, 91-100, 115-142, 160-180, 191-222, 225-258). In addition, there are PtdIns(4,5)P2-binding residues at aa 28, 38, 40, 41 (K, K, K, H).
AD: The AD has two subdomains: a central clathrin and adaptor protein binding (CLAP) domain and the remainder is an unnamed domain (ADΔCLAP). CLAP domain: aa 290-525, with CLAP motifs: DIF, DLL, DPF (see below), and FESVF: aa 488-493. Unnamed domain (ADΔCLAP): aa 526-652. ADΔCLAP is basic. The assembly domain (AD) has a role of clathrin and AP2 binding.
Other domains: transcriptional activation domain (TAD) (aa 408-572). PICALM is O-GlcNAc modified at aa 454 (S). Nuclear export signal (NES) LANLVGNLGI: aa 544-553. The NES consensus sequence is ΦX1-3ΦX2-3ΦXΦ, where Φ is most often leucine. The NES is the factor which contributes to PICALM/MLLT10 mediated leukemogenesis.
Protein interaction domains: PICALM binds directly to various vesicle associated membrane proteins: VAMP2 , VAMP3, VAMP4, VAMP7 and VAMP8. PIMREG (FAM64) interaction domain: aa 221-294; FHL2 interaction domain: aa 294-335; proteins with an EPS15 homology domain interaction domain: NPF (Asp-Pro-Phe) motif (aa 437-439). Clathrin binding motifs (CBM): Binding of clathrin heavy chain (CLTC) involves primarily aa 413-652, however, the entire AD is required for efficient clathrin binding. PICALM has one DLL (Asp-Leu-Leu) motif (aa 392-394); one DIF (Asp-Ile-Phe) motif (aa 375-377) which could bind clathrin, but also AP2A1 (AP2 alpha subunit); and one DPF (Asp-Pro-Phe) sequence (aa 420-422), which can also bind AP2A1. Other clathrin binding sequences involve L/I (Leu/Ile) in aa 540-553 and aa 649-652 (Tebar et al., 1999; Ford et al., 2001; Archangelo et al., 2006; Pašaliç et al., 2011; Moshkanbaryans et al., 2014; Moshkanbaryans et al., 2016).
Gene Name KMT2A
Location 11q23
Dna / Rna 37 exons, spanning about 120 kb; 13-15 mRNA
Protein 3969 amino acids, 431 kDa; Transcriptional regulatory factor. MLL is known to be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation (HOXA9 in particular).

Result of the chromosomal anomaly

Hybrid gene
Description The KMT2A breakpoint was in intron 9 in 2 cases, and in intron 10 in the 2 other cases (Meyer et al., 2013). The full-length KMT2A/PICALM transcript was 5409 bp long, including 4218 bp from KMT2A exons 1-7 and 1191 bp from PICALM (exons 8-20) in Wechsler et al., 2003.
  
Fusion Protein
 
Description The KMT2A/PICALM fusion protein contained 1803 amino acids and included 1406 amino acids from KMT2A A-T hooks and repression domain, and a PICALM-derived clathrin-binding domain in Wechsler et al., 2003.
  

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

The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10.
Archangelo LF, Gläsner J, Krause A, Bohlander SK.
Oncogene. 2006 Jul 6;25(29):4099-109.
PMID 16491119
 
Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes.
Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT.
Science. 2001 Feb 9;291(5506):1051-5.
PMID 11161218
 
The MLL recombinome of acute leukemias in 2013.
Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Emerenciano M, Pombo de Oliveira M, Renneville A, Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Vormoor J, Choi WW, Jarosova M, Kolenova A, Bueno C, Menendez P, Wehner S, Eckert C, Talmant P, Tondeur S, Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, Callanan MB, Cayuela JM, Herbaux C, Cazzaniga G, Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre P, Te Kronnie G, Schäfer BW, Kubetzko S, Alonso CN, zur Stadt U, Sutton R, Venn NC, Izraeli S, Trakhtenbrot L, Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke A, Stanulla M, Schrappe M, Sedék L, Szczepa?ski T, Zwaan CM, Coenen EA, van den Heuvel-Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, Marschalek R.
Leukemia. 2013 Nov;27(11):2165-76. doi: 10.1038/leu.2013.135.
PMID 23628958
 
The MLL recombinome of acute leukemias.
Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, den Boer ML, Pieters R, Ennas MG, Angelucci E, Koehl U, Greil J, Griesinger F, Zur Stadt U, Eckert C, Szczepa?ski T, Niggli FK, Schäfer BW, Kempski H, Brady HJ, Zuna J, Trka J, Nigro LL, Biondi A, Delabesse E, Macintyre E, Stanulla M, Schrappe M, Haas OA, Burmeister T, Dingermann T, Klingebiel T, Marschalek R.
Leukemia. 2006 May;20(5):777-84.
PMID 16511515
 
A Novel Sequence in AP180 and CALM Promotes Efficient Clathrin Binding and Assembly.
Moshkanbaryans L, Xue J, Wark JR, Robinson PJ, Graham ME.
PLoS One. 2016 Aug 30;11(8):e0162050. doi: 10.1371/journal.pone.0162050.
PMID 27574975
 
FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia.
Paöaliç Z, Greif PA, Jurinoviç V, Mulaw M, Kakadia PM, Tizazu B, Fröhlich-Archangelo L, Krause A, Bohlander SK.
Blood Cancer J. 2011 Nov;1(11):e42. doi: 10.1038/bcj.2011.40.
PMID 22829078
 
Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic.
Tebar F, Bohlander SK, Sorkin A.
Mol Biol Cell. 1999 Aug;10(8):2687-702.
PMID 10436022
 
A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein.
Wechsler DS, Engstrom LD, Alexander BM, Motto DG, Roulston D.
Genes Chromosomes Cancer. 2003 Jan;36(1):26-36.
PMID 12461747
 

Citation

This paper should be referenced as such :
Huret JL
t(11;11)(q14;q23) KMT2A/PICALM; inv(11)(q14q23) KMT2A/PICALM;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t1111q14q23ID1411.html


Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes PICALM KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 t(11;11)(q14;q23) KMT2A/PICALM

External links

Mitelman databaset(11;11)(q14;q23) [Case List]    t(11;11)(q14;q23) [Association List] Mitelman database (CGAP - NCBI)
arrayMapMorph ( 9891/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9807/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9813/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaset(11;11)(q14;q23) KMT2A/PICALM
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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indexed on : Tue Mar 14 14:22:59 CET 2017


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