Leukaemia Section

Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Mini Review t(11;11)(q14;q23) KMT2A/PICALM inv(11)(q14q23) KMT2A/PICALM Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France. jean- [email protected]

Published in Atlas Database: March 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1111q14q23ID1411.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68879/03-2017-t1111q14q23ID1411.pdf DOI: 10.4267/2042/68879

Otherwise, in a large study of cases of chromosomal Abstract rearrangements involving the human KMT2A Review on t(11;11)(q14;q23) and inv(11)(q14q23) (MLL) gene, a t(11;11)(q14;q23) or inv(11)(q14q23) KMT2A/PICALM, with data on clinics and the KMT2A/PICALM was found in 1 out of 440 infant genes involved. ALL patients, 1 out of 105 infant AML patients, 1 KEYWORDS out of 205 pediatric ALL patients, 1 out of 272 adult Chromosome 11; KMT2A; PICALM; acute myeloid AML patients, and none in 202 pediatric AML leukemia; acute lymphoblastic leukemia. patients, nor in 333 adult ALL patients (Meyer et al., 2013). Note: the case by Meyer et al., 2006 was Clinics and pathology reused in Meyer et al., 2013. Disease Genes involved and Acute myeloid leukemia (AML) and acute proteins lymphoblastic leukemia (ALL). Clinics PICALM (clathrin assembly lymphoid myeloid leukemia gene) There was the case of a 12-week-old female infant with acute monocytic leukemia (M5b) and Location inv(11)(q14q23), dead at day 11 (Wechsler et al., 11q14.2 2003). DNA/RNA 24 transcripts

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

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

KMT2A (myeloid/lymphoid or mixed 11q23.3 lineage leukemia) DNA/RNA Location 37 exons, spanning about 120 kb; 13-15 mRNA

Protein Hybrid gene 3969 amino acids, 431 kDa; Transcriptional Description regulatory factor. MLL is known to be associated The KMT2A breakpoint was in intron 9 in 2 cases, with more than 30 proteins, including the core and in intron 10 in the 2 other cases (Meyer et al., components of the SWI/SNF chromatin remodeling 2013). The full-length KMT2A/PICALM transcript complex and the transcription complex TFIID. MLL was 5409 bp long, including 4218 bp from KMT2A binds promotors of HOX genes through acetylation exons 1-7 and 1191 bp from PICALM (exons 8-20) and methylation of histones. MLL is a major in Wechsler et al., 2003. regulator of hematopoesis and embryonic development, through regulation of HOX genes Fusion protein expression regulation (HOXA9 in particular). Result of the chromosomal anomaly

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

CM, Coenen EA, van den Heuvel-Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, Marschalek R. The MLL recombinome of acute Description leukemias in 2013. Leukemia. 2013 Nov;27(11):2165-76 The KMT2A/PICALM fusion protein was contained 1803 amino acids and included 1406 Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S, Schoch C, Jansen MW, van Dongen JJ, den amino acids from KMT2A A-T hooks and repression Boer ML, Pieters R, Ennas MG, Angelucci E, Koehl U, Greil domain, and a PICALM-derived clathrin-binding J, Griesinger F, Zur Stadt U, Eckert C, Szczepański T, Niggli domain in Wechsler et al., 2003. 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, References Klingebiel T, Marschalek R. The MLL recombinome of acute leukemias. Leukemia. 2006 May;20(5):777-84 Archangelo LF, Gläsner J, Krause A, Bohlander SK. The novel CALM interactor CATS influences the subcellular Moshkanbaryans L, Xue J, Wark JR, Robinson PJ, Graham localization of the leukemogenic fusion protein CALM/AF10. ME. A Novel Sequence in AP180 and CALM Promotes Oncogene. 2006 Jul 6;25(29):4099-109 Efficient Clathrin Binding and Assembly. PLoS One. 2016;11(8):e0162050 Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT. Pašaliç Z, Greif PA, Jurinoviç V, Mulaw M, Kakadia PM, Simultaneous binding of PtdIns(4,5)P2 and clathrin by Tizazu B, Fröhlich-Archangelo L, Krause A, Bohlander SK. AP180 in the nucleation of clathrin lattices on membranes. FHL2 interacts with CALM and is highly expressed in acute Science. 2001 Feb 9;291(5506):1051-5 erythroid leukemia. Blood Cancer J. 2011 Nov;1(11):e42 Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Tebar F, Bohlander SK, Sorkin A. Clathrin assembly Emerenciano M, Pombo de Oliveira M, Renneville A, lymphoid myeloid leukemia (CALM) protein: localization in Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, endocytic-coated pits, interactions with clathrin, and the Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, impact of overexpression on clathrin-mediated traffic. Mol Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, Biol Cell. 1999 Aug;10(8):2687-702 Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Wechsler DS, Engstrom LD, Alexander BM, Motto DG, Vormoor J, Choi WW, Jarosova M, Kolenova A, Bueno C, Roulston D. A novel chromosomal inversion at 11q23 in Menendez P, Wehner S, Eckert C, Talmant P, Tondeur S, infant acute myeloid leukemia fuses MLL to CALM, a gene Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, that encodes a clathrin assembly protein. Genes Callanan MB, Cayuela JM, Herbaux C, Cazzaniga G, Chromosomes Cancer. 2003 Jan;36(1):26-36 Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre P, Te Kronnie G, This article should be referenced as such: Schäfer BW, Kubetzko S, Alonso CN, zur Stadt U, Sutton Huret JL. t(11;11)(q14;q23) KMT2A/PICALM; R, Venn NC, Izraeli S, Trakhtenbrot L, Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke inv(11)(q14q23) KMT2A/PICALM. Atlas Genet A, Stanulla M, Schrappe M, Sedék L, Szczepański T, Zwaan Cytogenet Oncol Haematol. 2018; 22(3):97-100.

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