t(11;11)(q14;q23) KMT2A/PICALM
inv(11)(q14q23) KMT2A/PICALM

2017-03-01   Jean-Loup Huret 

1.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.

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 (clathrin assembly lymphoid myeloid leukemia gene)
Location
11q14.2
Dna rna description
24 transcripts

Protein description
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 (myeloid/lymphoid or mixed lineage leukemia)
Location
11q23.3
Dna rna description
37 exons, spanning about 120 kb; 13-15 mRNA
Protein description
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

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.
Atlas Image

Description

The KMT2A/PICALM fusion protein was 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.

Highly cited references

Pubmed IDYearTitleCitations
323085882020Mutations within the Activation Loop Domain of FLT3 in Two Pediatric Patients with Refractory Infant Acute Myeloid Leukemia.0

Bibliography

Pubmed IDLast YearTitleAuthors
164911192006The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10.Archangelo LF et al
111612182001Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes.Ford MG et al
236289582013The MLL recombinome of acute leukemias in 2013.Meyer C et al
165115152006The MLL recombinome of acute leukemias.Meyer C et al
275749752016A Novel Sequence in AP180 and CALM Promotes Efficient Clathrin Binding and Assembly.Moshkanbaryans L et al
228290782011FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia.Pašaliç Z et al
104360221999Clathrin 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 et al
124617472003A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein.Wechsler DS et al

Summary

Fusion gene

KMT2A/PICALM

Citation

Jean-Loup Huret

t(11;11)(q14;q23) KMT2A/PICALM
inv(11)(q14q23) KMT2A/PICALM

Atlas Genet Cytogenet Oncol Haematol. 2017-03-01

Online version: http://atlasgeneticsoncology.org/haematological/1411/inv(11)(q14q23)

External Links