Table of Contents

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.1,2

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.3 KMT2D mutations were later reported in BL by Grande et al.4

Experimental Evidence

Driver mutations affecting this gene in BL/DLBCL/FL have been experimentally demonstrated to cause a reduction or loss of function (LOF).5

Relevance tier by entity

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Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 342 0.3140 [0.2865,0.3416]
DLBCL GAMBL with Reddy 2,088 565 0.2706 [0.2515,0.2896]
DLBCL BC 231 78 0.3377 [0.2767,0.3986]
DLBCL Dana-Farber 303 78 0.2574 [0.2082,0.3067]
DLBCL NCI 470 162 0.3447 [0.3017,0.3876]
DLBCL Reddy 999 223 0.2232 [0.1974,0.249]
DLBCL DLBCL_ICGC 85 24 0.2824 [0.1867,0.378]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 372 0.5794 [0.5413,0.6176]
FL GAMBL with Crouch 1,189 758 0.6375 [0.6102,0.6648]
FL BC 379 239 0.6306 [0.582,0.6792]
FL Kalmbach 164 75 0.4573 [0.3811,0.5336]
FL Crouch 547 386 0.7057 [0.6675,0.7439]
FL FL_ICGC 99 58 0.5859 [0.4888,0.6829]

BL

pathology Collection N mutated Incidence CI
BL GAMBL without Panea 309 30 0.0562 [0.0311,0.0813]
BL GAMBL without ICGC/Zhou 320 44 0.1364 [0.0988,0.1739]
BL GAMBL with Panea 410 46 0.0675 [0.0438,0.0911]
BL BLGSP 219 28 0.1279 [0.0836,0.1721]
BL Zhou/ICGC 90 2 0.0222 [0,0.0527]
BL Panea 101 16 0.1584 [0.0872,0.2296]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 0.4071 7.9165 0
FL 3.1476 131.9890 0
DLBCL 1.2871 25.1333 0

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Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-27 : Morin : FL 2012-08-27 : Rossi : MZL 2013-11-05 : Bea : MCL 2019-03-21 : Grande : BL 2019-08-20 : Desch : PMBL

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 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
2.
Desch AK, Hartung K, Botzen A, Brobeil A, Rummel M, Kurch L, Georgi T, Jox T, Bielack S, Burdach S, Classen CF, Claviez A, Debatin KM, Ebinger M, Eggert A, Faber J, Flotho C, Frühwald M, Graf N, Jorch N, Kontny U, Kramm C, Kulozik A, Kühr J, Sykora KW, Metzler M, Müller HL, Nathrath M, Nüßlein T, Paulussen M, Pekrun A, Reinhardt D, Reinhard H, Rössig C, Sauerbrey A, Schlegel PG, Schneider DT, Scheurlen W, Schweigerer L, Simon T, Suttorp M, Vorwerk P, Schmitz R, Kluge R, Mauz-Körholz C, Körholz D, Gattenlöhner S, Bräuninger A. Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma. Leukemia. 2020 Jan;34(1):151–166.
3.
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.
4.
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;133(12):1313–1324. PMCID: PMC6428665
5.
Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, Vlasevska S, Mo T, Tang H, Basso K, Ge K, Dalla-Favera R, Pasqualucci L. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med. 2015 Oct;21(10):1190–1198. PMCID: PMC5145002
6.
Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, Monti S, Vaisitti T, Arruga F, Famà R, Ciardullo C, Greco M, Cresta S, Piranda D, Holmes A, Fabbri G, Messina M, Rinaldi A, Wang J, Agostinelli C, Piccaluga PP, Lucioni M, Tabbò F, Serra R, Franceschetti S, Deambrogi C, Daniele G, Gattei V, Marasca R, Facchetti F, Arcaini L, Inghirami G, Bertoni F, Pileri SA, Deaglio S, Foà R, Dalla-Favera R, Pasqualucci L, Rabadan R, Gaidano G. The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012 Aug 27;209(9):1537–1551. PMCID: PMC3428941

Citing

If you use the information or data from this site, please cite

Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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