Regulation and Function of the E2A Proteins in B Cell Development

Murre, Cornelis

doi:10.1007/0-387-46530-8_1

Cited by 21 publications

(20 citation statements)

References 31 publications

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“…The transcription factor E2A is known to initiate the global gene expression profile of Blineage specification through the up-regulation of genes such as Ebf1 and Pax5 (Kee and Murre 1998;Murre 2007). If Ly6d expression correlates with the earliest step in B-cell specification, we would predict that expression of these B-cell-specifying factors would begin during the transition from Ly6d À ALPs to Ly6d + BLPs.…”

Section: Resultsmentioning

confidence: 99%

Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development

Inlay¹,

Bhattacharya²,

Sahoo³

et al. 2009

Genes Dev.

262

345

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Common lymphoid progenitors (CLPs) clonally produce both B-and T-cell lineages, but have little myeloid potential in vivo. However, some studies claim that the upstream lymphoid-primed multipotent progenitor (LMPP) is the thymic seeding population, and suggest that CLPs are primarily B-cell-restricted. To identify surface proteins that distinguish functional CLPs from B-cell progenitors, we used a new computational method of Mining Developmentally Regulated Genes (MiDReG). We identified Ly6d, which divides CLPs into two distinct populations: one that retains full in vivo lymphoid potential and produces more thymocytes at early timepoints than LMPP, and another that behaves essentially as a B-cell progenitor.Supplemental material is available at http://www.genesdev.org.

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Section: Resultsmentioning

confidence: 99%

Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development

Inlay¹,

Bhattacharya²,

Sahoo³

et al. 2009

Genes Dev.

262

345

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“…The latter suggests involvement of the single nucleotide polymorphism (SNP) in transcription, 85 possibly because the C Ͼ G SNP is located within a binding site for E47, the predominantly active isoform of E2A in human B lymphocytes that binds canonical E-box elements and activates gene transcription. 87 These events are essential in the programs regulating B-cell differentiation by controlling Ig gene transcription and recombination as well as expression of other B-lineage genes. 87 E47 is effectively recruited to the regulatory region of CD38 and the CD38 genotype in the E-box conditions the strength of the binding.…”

Section: Role Of Genetic Elementsmentioning

confidence: 99%

CD38 and chronic lymphocytic leukemia: a decade later

Malavasi

Deaglio

Damle

et al. 2011

Blood

193

160

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This review highlights a decade of investigations into the role of CD38 in CLL. CD38 is accepted as a dependable marker of unfavorable prognosis and as an indicator of activation and proliferation of cells when tested. Leukemic clones with higher numbers of CD38 ؉ cells are more responsive to BCR signaling and are characterized by enhanced migration. In vitro activation through CD38 drives CLL proliferation and chemotaxis via a signaling pathway that includes ZAP-70 and ERK1/2. Finally, CD38 is under a polymorphic transcriptional control after external signals.Consequently, CD38 appears to be a global molecular bridge to the environment, promoting survival/proliferation over apoptosis. Together, this evidence contributes to the current view of CLL as a chronic disease in which the host's microenvironment promotes leukemic cell growth and also controls the sequential acquisition and accumulation of genetic alterations. This view relies on the existence of a set of surface molecules, including CD38, which support proliferation and survival of B cells on their way to and after neoplastic transformation. The second decade of studies on CD38 in CLL will tell if the molecule is an effective target for antibody-mediated therapy in this currently incurable leukemia. (Blood. 2011;118(13):3470-3478)The current view of chronic lymphocytic leukemia (CLL) is that of a disease characterized by a dynamic balance between cells circulating in the blood and cells located in permissive niches in lymphoid organs. 1 The former are primarily mature-looking small lymphocytes resistant to apoptosis, whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment. 2 The heterogeneous clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genomic alterations. 3 Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. [4][5][6][7] Cell surface CD38 is one of these markers.This review highlights a decade of investigations into the role of CD38 in CLL. An association between CD38 expression by CLL cells and a more aggressive clinical behavior was first reported in 1999 4 and confirmed by several subsequent studies. [8][9][10][11][12] Consequently, determination of the percentage of CD38-expressing cells within a clone has become part of the workup of CLL patients in many clinical centers, 13 and it is generally accepted that CD38 ϩ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner. 4 The underlying question behind these clinical observations is why expression of this molecule on the cell surface would correlate with a worse clinical outcome. The most obvious possibility is that CD38 expression reflects events occurring in...

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“…1,2 Family members include E12 and E47, which are alternatively spliced products of the E2A gene (hereafter referred to collectively as E2A), HEB, and E2-2. Each member contains a C-terminal bHLH domain responsible for protein dimerization and recognition of the E-box DNA sequence CANNTG as well as 2 activation domains, AD1 and AD2, which function either independently or cooperatively depending on cell type to regulate target gene transcription through the recruitment of transcriptional coactivators and corepressors.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1

Denis

Chitayat

Plevin

et al. 2012

Blood

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E-proteins are critical transcription factors in B-cell lymphopoiesis. E2A, 1 of 3 E-protein–encoding genes, is implicated in the induction of acute lymphoblastic leukemia through its involvement in the chromosomal translocation 1;19 and consequent expression of the E2A-PBX1 oncoprotein. An interaction involving a region within the N-terminal transcriptional activation domain of E2A-PBX1, termed the PCET motif, which has previously been implicated in E-protein silencing, and the KIX domain of the transcriptional coactivator CBP/p300, critical for leukemogenesis. However, the structural details of this interaction remain unknown. Here we report the structure of a 1:1 complex between PCET motif peptide and the KIX domain. Residues throughout the helical PCET motif that contact the KIX domain are important for both binding KIX and bone marrow immortalization by E2A-PBX1. These results provide molecular insights into E-protein–driven differentiation of B-cells and the mechanism of E-protein silencing, and reveal the PCET/KIX interaction as a therapeutic target for E2A-PBX1–induced leukemia.

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Regulation and Function of the E2A Proteins in B Cell Development

Cited by 21 publications

References 31 publications

Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development

Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development

CD38 and chronic lymphocytic leukemia: a decade later

Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1

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