The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins

Lü, Gang; Middleton, Richard E.; Sun, Huahang; Naniong, MarkVic; Ott, Christopher J.; Mitsiades, Constantine S.; Wong, Kwok-Kin; Bradner, James E.; Kaelin, William G.

doi:10.1126/science.1244917

Cited by 1,223 publications

(1,187 citation statements)

References 33 publications

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“…Here, we have identified Rabex-5 as a Cereblon-interacting protein and IMiD target molecule. Our observations on the disruption of Cereblon-Rabex-5 binding differ substantially from previously identified interactions with Ikaros, CK1α, GS, or MEIS2 (10,17,(20)(21)(22). In particular, protein levels of Rabex-5 were not affected by loss of Cereblon binding.…”

Section: Discussioncontrasting

confidence: 55%

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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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Section: Discussioncontrasting

confidence: 55%

“…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%

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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“…Notably, IMiD-induced degradation of AIOLOS and IKAROS adversely affects the cellular fitness of MM cells (Kronke et al 2014a;Lu et al 2014). One can speculate that the IKAROS-and AIOLOS-based regulatory pathways that modulate pre-B-cell-bone marrow stromal interactions to provide a balance between self-renewal, survival, and differentiation may also be involved in the longevity of bone marrow plasma cells and their malignant counterparts.…”

Section: Ikaros Regulation Of Mature Lymphocyte Antigenic Responsesmentioning

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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“…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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The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins

Cited by 1,223 publications

References 33 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

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

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