Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells

Krönke, Jan; Udeshi, Namrata D.; Narla, Anupama; Grauman, Peter V.; Hurst, Slater N.; McConkey, Marie; Svinkina, Tanya; Heckl, Dirk; Comer, Eamon; Li, Xiaoyü; Ciarlo, Christie; Hartman, Emily C.; Munshi, Nikhil C.; Schenone, Monica; Schreiber, Stuart L.; Carr, Steven A.; Ebert, Benjamin L.

doi:10.1126/science.1244851

Cited by 1,504 publications

(1,432 citation statements)

References 31 publications

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“…Given the literature (20,21,23,24), we considered whether Rabex-5 is a substrate of CUL4A CRBN . However, protein levels of recombinant Rabex-5 were unaffected by IMiD treatment.…”

Section: Discussionmentioning

confidence: 99%

“…We suggest that these two observations might be explained if the binding of substrates to Cereblon prevents the formation of a complex with Rabex-5. Thus, according to this hypothesis, the first observation is explained by the IMiD-induced recruitment of substrates IKZF1, IKZF3, and CK1α (17,20,23), perhaps resulting in a conformational change that renders Cereblon incapable of binding Rabex-5. This system is present only in human systems.…”

Section: Discussionmentioning

confidence: 99%

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Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

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

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Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon–Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.

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“…Given the literature (20,21,23,24), we considered whether Rabex-5 is a substrate of CUL4A CRBN . However, protein levels of recombinant Rabex-5 were unaffected by IMiD treatment.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

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

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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).…”

mentioning

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.…”

mentioning

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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Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells

Cited by 1,504 publications

References 31 publications

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

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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Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells

Cited by 1,504 publications

References 31 publications

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

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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Product

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