Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage

Thal, Melissa; Carvalho, Thiago; He, Tao; Kim, Hyung‐Gyoon; Gao, Hua; Hagman, James; Klug, Christopher A.

doi:10.1073/pnas.0802550106

Cited by 79 publications

(68 citation statements)

References 40 publications

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“…E-proteins are antagonized by the Id proteins, which contain an HLH motif but lack a DNA binding region [30]. Furthermore, it has been documented that the downregulation of both Id2 and Id3 is an essential event in B-lineage specification although the loss of either factor was not sufficient to promote B cell development [31]. We observed significant changes in E2A, Id2 and Id3 in Nfix-deficient cells and upon ectopic Nfix expression.…”

Section: Discussionsupporting

confidence: 46%

NFIX expression critically modulates early B lymphopoiesis and myelopoiesis

Keeshan

O’Connor

Campos

et al. 2013

Experimental Hematology

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The commitment of stem and progenitor cells toward specific hematopoietic lineages is tightly controlled by a number of transcription factors that regulate differentiation programs via the expression of lineage restricting genes. Nuclear factor one (NFI) transcription factors are important in regulating hematopoiesis and here we report an important physiological role of NFIX in B-and myeloid lineage commitment and differentiation. We demonstrate that NFIX acts as a regulator of lineage specification in the haematopoietic system and the expression of Nfix was transcriptionally downregulated as B cells commit and differentiate, whilst maintained in myeloid progenitor cells. Ectopic Nfix expression in vivo blocked early B cell development stage, coincident with the stage of its downregulation. Furthermore, loss of Nfix resulted in the perturbation of myeloid and lymphoid cell differentiation, and a skewing of gene expression involved in lineage fate determination. Nfix was able to promote myeloid differentiation of total bone marrow cells under B cell specific culture conditions but not when expressed in the hematopoietic stem cell (HSPC), consistent with its role in HSPC survival. The lineage choice determined by Nfix correlated with transcriptional changes in a number of genes, such as E2A, C/EBP, and Id genes. These data highlight a novel and critical role for NFIX transcription factor in hematopoiesis and in lineage specification.

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Section: Discussionsupporting

confidence: 46%

NFIX expression critically modulates early B lymphopoiesis and myelopoiesis

Keeshan

O’Connor

Campos

et al. 2013

Experimental Hematology

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“…However, the BLP population encompasses a much larger fraction of CLPs than is indicated by l5 reporter expression, demonstrating that Ly6d up-regulation is the earliest mark of B-cell specification identified to date, prior to B220, CD19, or l5 expression. As shown by others ), a significant fraction of CLPs express Ebf1, which may play a role in initiating B-cell specification, perhaps by suppressing Id2/Id3 expression (Thal et al 2009). As Ebf1 expression increases dramatically between the ALP and BLP populations, we suspect that the majority of Ebf1-expressing cells are contained within the BLP population.…”

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.

271

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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“…1E). It has been previously shown that down-regulation of Id2 is essential for B-cell commitment and its up-regulation in mouse bone marrow blocks B cells at the prepro-B stage (22). Another target of Bcl6, Ccl3, or Mip-1α is involved in the acute inflammatory state in the recruitment and activation of polymorphonuclear leukocytes.…”

Section: Resultsmentioning

confidence: 99%

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu

Volinia

Costinean

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

121

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Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.NfκB | Ingenuity Pathway Analysis M icroRNAs (miRNAs) are 18-24-nucleotide-long noncoding RNA molecules that regulate gene expression in many cellular processes including proliferation, differentiation, and development. Recent studies have established that expression of miRNAs is widely altered in a variety of cancers and miR-155 is one of the most frequently overexpressed miRNAs in various solid and hematological malignancies (1). miR-155 is highly upregulated in Hodgkin, primary mediastinal, and diffuse large B-cell lymphomas (DLBCL) (2, 3) and is almost absent or significantly down-regulated in primary cases of Burkitt lymphoma (4). Overexpression of bic, host mRNA of miR-155, caused increased incidence of leukemia and a decrease in latency of lymphoma development in chickens with elevated levels of MYC (5). Overexpression of miR-155 in mice B cells (Eμ-miR-155) has been shown to cause pre-B-cell leukemia/high-grade lymphoma (6), whereas deletion of bic/miR-155 in mice has been attributed to immunodeficiency and impaired T-cell-dependent antibody response (7,8). Additionally, sustained miR-155 expression in stem cell progenitors induced a myeloproliferative disease in transplanted mice (9). Despite the availability of multiple animal models and a ...

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Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage

Cited by 79 publications

References 40 publications

NFIX expression critically modulates early B lymphopoiesis and myelopoiesis

NFIX expression critically modulates early B lymphopoiesis and myelopoiesis

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

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

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