Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide

Zhu, Yuan Xiao; Braggio, Esteban; Shi, Chao; Bruins, Laura A.; Schmidt, Jessica; Wier, Scott Van; Chang, Xiu Bao; Bjorklund, Chad C.; Fonseca, Rafaël; Bergsagel, P. Leif; Orłowski, Robert Z.; Stewart, A. Keith

doi:10.1182/blood-2011-05-356063

Cited by 551 publications

(548 citation statements)

References 19 publications

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“…CC-220 is structurally related to lenalidomide and pomalidomide that show antiproliferative and immunomodulatory effects on B and T cells (118,119). Similar to lenalidomide and pomalidomide, which bind to CRBN, a critical component of a ubiquitin E3 CRL4 CRBN complex (120,121), CC-220 binds to CRBN to promote recruitment of Ikaros and Aiolos to CRL4 CRBN and the subsequent enhancement of the ubiquitination and degradation of these transcription factors (55-57).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Bortezomib is a proteasome inhbitor [39][40][41]; the mechanism of action of thalidomide and lenalidomide is unclear, but they are considered immunomodulatory agents [42] and may require cereblon (the putative primary teratogenic target for thalidomide) [43] expression for their anti-myeloma activity [44].…”

Section: Risk-adapted Therapymentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end‐organ damage.Risk stratificationIn the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk.Risk‐adapted initial therapyStandard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard‐risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.Maintenance therapyAfter initial therapy, lenalidomide maintenance is considered for standard‐risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in pateints with intermediate or high‐risk myeloma.Management of refractory diseasePatients with indolent relapse can be treated first with two‐drug or three‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.

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“…Stewart and colleagues first reported that RNAi knockdown of CRBN in multiple myeloma cells results in nearly complete cancellation of the anti-myeloma effects of IMiDs [23]. Furthermore, some patients who had become resistant to lenalidomide were found to have decreased expression of CRBN.…”

Section: Therapeutic Effects Of Imids Via Crbnmentioning

confidence: 99%

Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs

Ito

Handa

2016

Int J Hematol

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Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide

Cited by 551 publications

References 19 publications

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

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

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs

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