Immunomodulatory agents lenalidomide and pomalidomide co‐stimulate <scp>T</scp> cells by inducing degradation of <scp>T</scp> cell repressors <scp>I</scp>karos and <scp>A</scp>iolos via modulation of the <scp>E</scp>3 ubiquitin ligase complex <scp>CRL</scp>4<scp><sup>CRBN</sup></scp>

Gandhi, Anita K.; Kang, Jian; Havens, Courtney G.; Conklin, Thomas A.; Ning, Yuhong; Wu, Lang; Ito, Takumi; Ando, Hideki; Waldman, Michelle F.; Thakurta, Anjan; Klippel, Anke; Handa, Hiroshi; Daniel, Thomas O.; Schäfer, Peter; Chopra, Rajesh

doi:10.1111/bjh.12708

Cited by 532 publications

(297 citation statements)

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“…This results in IKAROS and AIOLOS protein degradation and interferes with MM cell growth (Gandhi et al 2014;Kronke et al 2014a,b). The second DNA-binding zinc finger (F2) in IKAROS and AIOLOS binds to the hydrophobic pocket of CEREBLON (the E3 ligase adaptor) when it is occupied by lenalidomide ( Fig.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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Lymphocyte differentiation is set to produce myriad immune effector cells with the ability to respond to multitudinous foreign substances. The uniqueness of this developmental system lies in not only the great diversity of cellular functions that it can generate but also the ability of its differentiation intermediates and mature effector cells to expand upon demand, thereby providing lifelong immunity. Surprisingly, the goals of this developmental system are met by a relatively small group of DNA-binding transcription factors that work in concert to control the timing and magnitude of gene expression and fulfill the demands for cellular specialization, expansion, and maintenance. The cellular and molecular mechanisms through which these lineage-promoting transcription factors operate have been a focus of basic research in immunology. The mechanisms of development discerned in this effort are guiding clinical research on disorders with an immune cell base. Here, I focus on IKAROS, one of the earliest regulators of lymphoid lineage identity and a guardian of lymphocyte homeostasis.

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Section: Post-translational Modificationsmentioning

confidence: 99%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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“…CC-220 is a modulator of the cullin ring ligase 4-cereblon (CRL4 CRBN ) E3 ubiquitin ligase complex, which induces ubiquitination of the CRBN substrates Aiolos (encoded by the gene IKZF3) and Ikaros (encoded by the gene IKZF1), resulting in their proteasomal degradation (55)(56)(57). Although thalidomide and related compounds bind both murine and human CRBN, only human CRBN induces ubiquitination and degradation of Aiolos and Ikaros (58).…”

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confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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“…This binding alters the substrate specificity of CRBN-containing ubiquitin ligase complexes (6, 7) even though IMiDs reduce the overall activity of E3 ubiquitin ligase (1). As a result, binding promotes abnormal degradation of the Ikaros zinc finger proteins 1 and 3 (IKZF1 and IKZF3), which in turn increases IL-2 production in T cells (6)(7)(8). However, although the CRBN-mediated effects of IMiDs are known, the physiological role of CRBN in T cells remains unclear.…”

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confidence: 99%

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 ⁺ T-cell activation

Kang

Park

Jeong

et al. 2016

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

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The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4+ T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells. CRBN binds directly to conserved DNA elements adjacent to Kcna3 via a previously uncharacterized DNA-binding motif. Consequently, in the absence of CRBN, the expression of Kv1.3 is derepressed, resulting in increased Kv1.3 expression, potassium flux, and CD4+ T-cell hyperactivation. In addition, experimental autoimmune encephalomyelitis in T-cell–specific Crbn-deficient mice was exacerbated by increased T-cell activation via Kv1.3. Thus, CRBN limits CD4+ T-cell activation via epigenetic regulation of Kv1.3 expression.

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Immunomodulatory agents lenalidomide and pomalidomide co‐stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4^CRBN

Cited by 532 publications

References 32 publications

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 ⁺ T-cell activation

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Immunomodulatory agents lenalidomide and pomalidomide co‐stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN

Cited by 532 publications

References 32 publications

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 + T-cell activation

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Immunomodulatory agents lenalidomide and pomalidomide co‐stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4^CRBN

Epigenetic regulation of Kcna3 -encoding Kv1.3 potassium channel by cereblon contributes to regulation of CD4 ⁺ T-cell activation