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Highlights d Intrinsic apoptosis controls the lifespan of FoB but not of MZB cells d Abrogation of apoptosis in mature B cells raises competition for BAFF in vivo d Heightened competition for BAFF compromises the physiology of FoB and MZB cells

Short running title: B cell responses require DOT1L. Abbreviations used: AID -activation-induced cytidine deaminase; ASCs -antibody-secreting cells; BCL6 -B cell lymphoma-6; CPM -counts per million; CTV -cell trace violet; DOT1Ldisruptor of telomeric silencing 1-like, EZH2 -enhancer of zeste homolog 2; FVS -fixable viability stain; H3K27me3 -trimethylation of lysine 27 on histone H3; Ig -immunoglobulin; KLH -Keyhole Limpet Hemocyanin; MLLr-ALL -Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia; NP -(4-Hydroxy-3-nitrophenyl)-acetyl; PRC2 -polycomb repressive complex 2; S1PR -sphingosine-1-phosphate receptor; Th cells -T helper cells. ABSTRACT Histone modifiers are essential molecular regulators that underpin the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L induces oncogenic gene expression in a subset of B cell leukemia. Despite its importance, little is known about its role in the humoral immune system. Herein, we demonstrate that DOT1L is a critical regulator of B cell biology. Dot1l f/f Mb1 Cre/+ mice had a block in B cell development, culminating in a significant reduction of mature B cells in the periphery. Upon immunization or influenza infection, germinal centers failed to form in Dot1l f/f Cd23 Cre/+ mice. Consequently, immunized mice revealed that DOT1L was essential for the formation of B cell memory populations. Dot1l deletion significantly attenuated the formation of class-switched antibody-secreting cells in both T-dependent and T-independent responses. Transcriptome, pathway and histological analysis identified a key role for DOT1L in reprogramming gene expression for migration and localization during the initial stages of a humoral response. Together, these results demonstrate an essential role for DOT1L in antigen-dependent B cell differentiation and hence, in generating an effective and lasting humoral immune response.