MEF2B

Overview

MEF2B is one of a number of genes affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. MEF2B mutations are observed in a significant subset of follicular lymphoma cases, as well as in other B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and MCL.^1,2 MEF2B has known hotspot mutations that affect multiple distinct domains of the protein.

Experimental Evidence

Thus far, there is limited information about the consequence of MEF2B mutations in DLBCL, FL or MCL. One study showed that MEF2B mutations lead to deregulation of BCL6 expression.³

Relevance tier by entity

Entity	Tier	Description
	1	High-confidence DLBCL gene
	1	High-confidence FL gene
	1	High-confidence MCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity	Collection	N	mutated	Incidence	95% CI
DLBCL	GAMBL without Reddy	1,089	104	0.0955	[0.078,0.113]
DLBCL	GAMBL with Reddy	2,088	163	0.0781	[0.0666,0.0896]
DLBCL	BC	231	26	0.1126	[0.0718,0.1533]
DLBCL	Dana-Farber	303	22	0.0726	[0.0434,0.1018]
DLBCL	NCI	470	46	0.0979	[0.071,0.1247]
DLBCL	Reddy	999	59	0.0591	[0.0444,0.0737]
DLBCL	DLBCL_ICGC	85	10	0.1176	[0.0492,0.1861]

FL

pathology	Collection	N	mutated	Incidence	CI
FL	GAMBL without Crouch	642	83	0.1293	[0.1033,0.1552]
FL	GAMBL with Crouch	1,189	176	0.1480	[0.1278,0.1682]
FL	BC	379	43	0.1135	[0.0815,0.1454]
FL	Kalmbach	164	29	0.1768	[0.1184,0.2352]
FL	Crouch	547	93	0.1700	[0.1385,0.2015]
FL	FL_ICGC	99	11	0.1111	[0.0492,0.173]

MCL

pathology	Collection	N	mutated	Incidence	CI
MCL	GAMBL	160	9	0.0512	[0.0172,0.0853]
MCL	BC_MCL	103	7	0.0680	[0.0194,0.1166]
MCL	Barcelona	57	2	0.0351	[0,0.0829]

Mutation pattern and selective pressure estimates

Entity	Missense dN/dS	Nonsense dN/dS	Q value
BL	0.9048	0.0000	1
FL	48.7008	24.2563	0
DLBCL	9.3155	15.4294	0

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr19	19279635	19281441	TSS	active_promoter

MEF2B Hotspots

DNA-Binding Domain (MADS-box and MEF2 Domain):

R24 (Arginine 24) A recurrent hotspot mutation. This position is located within the MADS-box domain, which is crucial for DNA binding and dimerization with other MEF2 family members.

R30 (Arginine 30) Another recurrent hotspot in the MADS-box domain. Mutations at this site can disrupt DNA binding and affect the transcriptional activity of MEF2B.

Transcriptional Activation Domain:

N81 (Asparagine 81) A mutation hotspot within the transcriptional activation domain. Alterations at this position can enhance the transcriptional activity of MEF2B, contributing to the overexpression of target genes involved in cell survival and proliferation.

Structure with HotMAPS hotspots

Functional Impact of MEF2B Mutations

Altered Transcriptional Activity:

Mutations in the DNA-binding domain, such as those at R24 and R30, can alter the binding affinity and specificity of MEF2B for its target DNA sequences. This can lead to changes in the expression of genes that are critical for cell growth, differentiation, and survival. Mutations in the transcriptional activation domain, like N81, can enhance the ability of MEF2B to activate transcription, which may lead to the upregulation of oncogenes and survival pathways.

MEF2B Hot Spots from GAMBL

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr19	19260066	T>C	H76R
chr19	19260064	C>T	E77K
chr19	19260050	G>T	N81K
chr19	19260045	T>G	D83A
chr19	19260045	T>C	D83G
chr19	19260045	T>A	D83V
chr19	19260042	A>G	I84T

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-27 : Morin : DLBCL 2013-11-05 : Bea : MCL

References

Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJM, Connors JM, Hirst M, Gascoyne RD, Marra MA. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011 Jul 27;476(7360):298–303. PMCID: PMC3210554

Beà S, Valdés-Mas R, Navarro A, Salaverria I, Martín-Garcia D, Jares P, Giné E, Pinyol M, Royo C, Nadeu F, Conde L, Juan M, Clot G, Vizán P, Croce LD, Puente DA, López-Guerra M, Moros A, Roue G, Aymerich M, Villamor N, Colomo L, Martínez A, Valera A, Martín-Subero JI, Amador V, Hernández L, Rozman M, Enjuanes A, Forcada P, Muntañola A, Hartmann EM, Calasanz MJ, Rosenwald A, Ott G, Hernández-Rivas JM, Klapper W, Siebert R, Wiestner A, Wilson WH, Colomer D, López-Guillermo A, López-Otín C, Puente XS, Campo E. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. PNAS. 2013;110(45):18250–18255.

Ying CY, Dominguez-Sola D, Fabi M, Lorenz IC, Bansal M, Califano A, Pasqualucci L, Basso K, Dalla-Favera R. MEF2B Mutations Lead to De-Regulated Expression of the BCL6 Oncogene in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma. Blood. 120.