KMT2D

Overview

KMT2D (also known as MLL2) encodes a histone H3K4 methyltransferase, playing a crucial role in germinal center B cell development and function. Mutations in KMT2D are among the most common mutations in FL and are also common in DLBCL.¹ KMT2D mutations are recurrent but less common in BL and MCL and many other B-cell neoplasms. Mutations typically cause loss of KMT2D function, leading to diminished H3K4 methylation, impacting gene expression that favours lymphomagenesis. KMT2D mutations are associated with poor prognosis in DLBCL.^2,3

History

First identified as mutated in DLBCL and FL in 2011 by Morin et al.¹ Mutations were later described in MCL in 2013 by Bea et al.⁴ KMT2D mutations were later reported in BL by Grande et al.⁵

Relevance tier by entity

Entity	Tier	Description
	1	high-confidence FL gene
	1	high-confidence DLBCL gene
	1	high-confidence BL gene
	1	high-confidence MCL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
FL	GAMBL genomes	67.67
DLBCL	GAMBL genomes	33.46
DLBCL	Schmitz cohort	34.47
DLBCL	Reddy cohort	22.32
DLBCL	Chapuy cohort	26.07
BL	GAMBL genomes+capture	11.32
BL	Thomas cohort	14.00
BL	Panea cohort	15.80
MCL	GAMBL genomes	16.59

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	No	Yes	0.689	13.459
DLBCL	No	Yes	3.731	104.190
FL	No	Yes	20.755	1353.812

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

KMT2D Expression

References

1. 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 SJ, 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. doi: 10.1038/nature10351. PMID: 21796119; PMCID: PMC3210554.
2. You, H., Xu-Monette, Z., Wei, L., Nunns, H., Nagy, M., Bhagat, G., Fang, X., Zhu, F., Visco, C., Tzankov, A., Dybkaer, K., Chiu, A., Tam, W., Zu, Y., Hsi, E., Hagemeister, F., Huh, J., Ponzoni, M., Ferreri, A., Møller, M., Parsons, B., Krieken, J., Piris, M., Winter, J., Li, Y., Au, Q., Xu, B., Albitar, M., & Young, K. (2021). Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma. Oncoimmunology, 10. https://doi.org/10.1080/2162402X.2021.1928365.
3. Rushton CK, Arthur SE, Alcaide M, Cheung M, Jiang A, Coyle KM, Cleary KLS, Thomas N, Hilton LK, Michaud N, Daigle S, Davidson J, Bushell K, Yu S, Rys RN, Jain M, Shepherd L, Marra MA, Kuruvilla J, Crump M, Mann K, Assouline S, Connors JM, Steidl C, Cragg MS, Scott DW, Johnson NA, Morin RD. Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma. Blood Adv. 2020 Jul 14;4(13):2886-2898. doi: 10.1182/bloodadvances.2020001696. PMID: 32589730; PMCID: PMC7362366.
4. 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 Nov 5;110(45):18250–18255. PMID: 24145436
5. Grande BM, Gerhard DS, Jiang A, Griner NB, Abramson JS, Alexander TB, Allen H, Ayers LW, Bethony JM, Bhatia K, Bowen J, Casper C, Choi JK, Culibrk L, Davidsen TM, Dyer MA, Gastier-Foster JM, Gesuwan P, Greiner TC, Gross TG, Hanf B, Harris NL, He Y, Irvin JD, Jaffe ES, Jones SJM, Kerchan P, Knoetze N, Leal FE, Lichtenberg TM, Ma Y, Martin JP, Martin MR, Mbulaiteye SM, Mullighan CG, Mungall AJ, Namirembe C, Novik K, Noy A, Ogwang MD, Omoding A, Orem J, Reynolds SJ, Rushton CK, Sandlund JT, Schmitz R, Taylor C, Wilson WH, Wright GW, Zhao EY, Marra MA, Morin RD, Staudt LM. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood. 2019 Mar 21;133(12):1313–1324.