EBF1 drives hallmark B cell gene expression by enabling the interaction of PAX5 with the MLL H3K4 methyltransferase complex

Bullerwell, Charles E.; Robichaud, Philippe Pierre; Deprez, Pierre; Joy, Andrew P.; Wajnberg, Gabriel; D’souza, Darwin; Chacko, Simi; Fournier, Sébastien; Crapoulet, Nicolas; Barnett, David A.; Lewis, Stephen M.; Ouellette, Rodney J.

doi:10.1038/s41598-021-81000-5

Cited by 22 publications

(19 citation statements)

References 48 publications

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“…7c). Twenty-four percent of total B cellspecific TFs are shared between the two organisms including Tcf4 [38][39][40][41], Pax5 [78][79][80], Bhlhe41 [81][82][83], and several Irf family TFs (Irf4, Irf5, Irf8) [24,84,85]. This relatively large overlapping percentage is consistent with the clustering of B cells across species shown in Fig.…”

Section: Systematic Comparison Between Human and Mouse Immune Cells R...supporting

confidence: 69%

Systems-level identification of key transcription factors in immune cell specification

Liu

Omilusik

Toma

et al. 2022

Preprint

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SummaryTranscription factors (TFs) are crucial for regulating cell differentiation during the development of the immune system. However, the key TFs for orchestrating the specification of distinct immune cells are not fully understood. Here, we integrated the transcriptomic and epigenomic measurements in 73 mouse and 61 human primary cell types, respectively, that span the immune cell differentiation pathways. We constructed the cell-type-specific transcriptional regulatory network and assessed the global importance of TFs based on the Taiji framework, which is a method we have previously developed that can infer the global impact of TFs using integrated transcriptomic and epigenetic data. Integrative analysis across cell types revealed putative driver TFs in cell lineage-specific differentiation in both mouse and human systems. We have also identified TF combinations that play important roles in specific developmental stages. Furthermore, we validated the functions of predicted novel TFs in murine CD8+ T cell differentiation and showed the importance of Elf1 and Prdm9 in the effector versus memory T cell fate specification and Kdm2b and Tet3 in promoting differentiation of CD8+ tissue resident memory (Trm) cells, validating the approach. Thus, we have developed a bioinformatic approach that provides a global picture of the regulatory mechanisms that govern cellular differentiation in the immune system and aids the discovery of novel mechanisms in cell fate decisions.

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Section: Systematic Comparison Between Human and Mouse Immune Cells R...supporting

confidence: 69%

Systems-level identification of key transcription factors in immune cell specification

Liu

Omilusik

Toma

et al. 2022

Preprint

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“…Although MEF2D mutation results in maturation arrest at the pre-B stage, its distinct immunophenotype is recognized to overlap with both early and late B progenitor stages 20 . The similarity of cell signals in PAX5 and KMT2A mutant B-ALL may represent the intimate relationship of KMT2A and PAX5 in regulating B lymphopoiesis 21 .…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Khabirova

Jardine

Coorens

et al. 2022

Nat Med

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KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid–lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.

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“…Presence of PAX5 on chromatin correlated with increased active chromatin marks in PAX5induced genes, whereas an inverse pattern of histone modifications was observed in PAX5-repressed genes [281]. As demonstrated later, another B-cell specific transcription factor, EBF1, is required for the interaction of PAX5 with the MLL H3K4 methyltransferase complex and subsequent epigenetic modifications [282]. EBF1 and PAX5 have opposing roles in normal and malignant B cells with regards to the regulation of the MYC oncogene.…”

Section: Exploiting Enhancers By Deregulated Transcription Factorsmentioning

confidence: 76%

Enhancing B-Cell Malignancies—On Repurposing Enhancer Activity towards Cancer

Kasprzyk

Sura

Dzikiewicz‐Krawczyk

2021

Cancers

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B-cell lymphomas and leukemias derive from B cells at various stages of maturation and are the 6th most common cancer-related cause of death. While the role of several oncogenes and tumor suppressors in the pathogenesis of B-cell neoplasms was established, recent research indicated the involvement of non-coding, regulatory sequences. Enhancers are DNA elements controlling gene expression in a cell type- and developmental stage-specific manner. They ensure proper differentiation and maturation of B cells, resulting in production of high affinity antibodies. However, the activity of enhancers can be redirected, setting B cells on the path towards cancer. In this review we discuss different mechanisms through which enhancers are exploited in malignant B cells, from the well-studied translocations juxtaposing oncogenes to immunoglobulin loci, through enhancer dysregulation by sequence variants and mutations, to enhancer hijacking by viruses. We also highlight the potential of therapeutic targeting of enhancers as a direction for future investigation.

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EBF1 drives hallmark B cell gene expression by enabling the interaction of PAX5 with the MLL H3K4 methyltransferase complex

Cited by 22 publications

References 48 publications

Systems-level identification of key transcription factors in immune cell specification

Systems-level identification of key transcription factors in immune cell specification

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Enhancing B-Cell Malignancies—On Repurposing Enhancer Activity towards Cancer

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