Differential Role for Cyclic AMP Response Element Binding Protein-1 in Multiple Stages of B Cell Development, Differentiation, and Survival

Chen, Hui-Chen; Byrd, John C.; Muthusamy, Natarajan

doi:10.4049/jimmunol.176.4.2208

Cited by 22 publications

(17 citation statements)

References 65 publications

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“…Transgenic mice overexpressing a dominant-negative CREB (Ser119-to-Ala mutant) in a B cell-specific manner showed a developmental block in the transition of pro-to pre-B cells (Chen et al, 2006). In contrast to CREB, single deficiency of the Elk members Elk1, Elk3, and Elk4 resulted in apparently normal B cell development, although this has not been analyzed in detail (Cesari et al, 2004;Costello et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

Erk Kinases Link Pre-B Cell Receptor Signaling to Transcriptional Events Required for Early B Cell Expansion

et al. 2008

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The pre-B cell receptor (pre-BCR) plays a crucial role in the development of immature B cells. Although certain aspects of proximal pre-BCR signaling have been studied, the intermediate signal transducers and the distal transcription modulators are poorly characterized. Here, we demonstrate that deletion of both Erk1 and Erk2 kinases was associated with defective pre-BCR-mediated cell expansion as well as a block in the transition of pro-B to pre-B cells. Phosphorylation of transcription factors Elk1 and CREB was mediated by Erk, and a dominant-negative mutation in the Erk-mediated phosphorylation sites of Elk1 or CREB suppressed pre-BCR-mediated cell expansion as well as expression of genes including Myc, which is involved in the cell-cycle progression. Together, our results identify a crucial role for Erk kinases in regulating B cell development by initiating transcriptional regulatory network and thereby pre-BCR-mediated cell expansion.

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Section: Discussionmentioning

confidence: 98%

Erk Kinases Link Pre-B Cell Receptor Signaling to Transcriptional Events Required for Early B Cell Expansion

et al. 2008

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“…24 B-cell restricted hCD37 expression is driven by immunoglobulin (Ig) V H promoter and Ig H -μ enhancer elements in the pBH expression vector. 24 The transgenic construct was generated by ligating the cDNA sequence of human CD37 (with an additional FLAG sequence) into EcoRI and NotI sites within the pBH vector. To generate our leukemia model, we crossed hemizygous hCD37-Tg mice with homozygous Eμ-TCL1 mice (C57BL/6 background) that have been previously described.…”

Section: Methodsmentioning

confidence: 99%

The CD37-targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

et al. 2014

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Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. While several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood, and promotes killing by macrophages and NK cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.

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“…Transgenic mice overexpressing a dominantlynegative CREB (Ser119 to Ala mutation) in a B cell-specific manner showed a developmental block in the transition from pro-to pre-B cells. 48 In contrast to CREB, deficiency of a single Elk member resulted in apparently normal B cell development. 49,50 However, it is possible that a certain degree of functional compensation between Elk1, Elk3 and Elk4 may exist, thereby modulating the phenotype.…”

Section: Erk Signaling In the Nucleusmentioning

confidence: 99%

Regulation of lymphocyte fate by Ras/ERK signals

Yasuda

Kurosaki

2008

Cell Cycle

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The Ras-ERK cascade is activated by countless external cues that stimulate diverse receptors. Therefore, the mechanisms by which distinct receptors dictate different cellular outcomes by activating the same signaling module has long fascinated many researchers. Initial clues came from observations that the duration of ERK activation is critical to cell-fate decisions. In classical experiments, PC12 cells proliferated after transient ERK activation by epidermal growth factor, but terminally differentiated after more sustained ERK activation by nerve growth factor. Subsequent studies suggested that the duration of ERK signaling is interpreted by cells through a network of immediate-early genes. Nevertheless, it remains ill-defined how the duration and strength of Ras-ERK signaling is established and what genes are differently regulated, thereby translating the response into different biological outcomes. Recent studies with lymphocytes have evoked a new idea that two types of interconnected mechanisms can contribute to the sensitivity and robustness of the ERK activity; (1) interplay between two types of Ras activators (Sos and RasGRP); (2) existence of two subcellular compartments for Ras activation (plasma membrane and Golgi). Moreover, candidate immediate early genes that regulate lymphocyte proliferation and differentiation have emerged.

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Differential Role for Cyclic AMP Response Element Binding Protein-1 in Multiple Stages of B Cell Development, Differentiation, and Survival

Cited by 22 publications

References 65 publications

Erk Kinases Link Pre-B Cell Receptor Signaling to Transcriptional Events Required for Early B Cell Expansion

Erk Kinases Link Pre-B Cell Receptor Signaling to Transcriptional Events Required for Early B Cell Expansion

The CD37-targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

Regulation of lymphocyte fate by Ras/ERK signals

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