Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs

2019 ◽  
Vol 19 (1) ◽  
pp. 51-78 ◽  
Author(s):  
Ota Fuchs
Keyword(s):  
Clinical Trials ◽  
Transcription Factors ◽  
Ubiquitin Ligase ◽  
Mononuclear Cells ◽  
E3 Ubiquitin Ligase ◽  
Lymphocytic Leukemia ◽  
Monocarboxylate Transporter ◽  
Immunomodulatory Drugs ◽  
Monocarboxylate Transporter 1 ◽  
Argonaute 2

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

scholarly journals Cereblon and Redox in Plasma Cells

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-9-SCI-9
Author(s):  
Florian Bassermann
Keyword(s):  
Multiple Myeloma ◽  
Ubiquitin Ligase ◽  
Plasma Cells ◽  
Predictive Biomarkers ◽  
Membrane Receptors ◽  
Monocarboxylate Transporter ◽  
Immunomodulatory Drugs ◽  
Myeloma Cells ◽  
H2o2 Decomposition ◽  
Monocarboxylate Transporter 1

Abstract The protein Cereblon (CRBN) has recently attracted considerable interest by virtue of its ability to mediate both anti-tumor as well as teratogenic activities of immunomodulatory drugs (IMiDs) 1-3 . Certain IMiDs have been shown to re-direct CRBN-associated ubiquitylation activity towards neo-substrates such as IKZF1/3 and CK1a, thereby promoting their proteasomal degradation 4-8. This mechanism has been implicated in the anti-proliferative effects of IMiDs in multiple myeloma (MM) and del(5q)-MDS. However, the pleiotropic anti-tumor effects of IMiDs, their adverse effects such as teratogenicity and neurotoxicity, and their synergy with proteasome inhibitors suggests further mechanisms of action. Previous research on CRBN has revealed novel insights that shed light on the physiological functions of this versatile protein in plasma cells. Indeed, next to its function as a ubiquitin ligase, CRBN has been shown to exist in ubiquitin-ligase independent complexes, where it functions as a chaperone for crucial trans-membrane receptors such as CD147 (also known as Basigin) and MCT1 (monocarboxylate transporter 1) 9. This functions links CRBN to the regulation of angiogenesis, cell invasion and particularly cell metabolism by governing lactate homeostasis. Likewise, CRBN has been implicated in the regulation of TrxR (thioredoxin reductase), thereby critically determining the redox balance in plasma cells 10. These findings have important implications for our understanding of IMiD biology and for the development of novel treatment approaches and predictive biomarkers for MM. Indeed, IMiDs inhibit the chaperone function of CRBN in a competitive manner and attenuate TrxR via CRBN, thereby preventing intracellular H2O2 decomposition. In turn, CRBN-dependent degradation of IKZF1 and IKZF3 have been shown to be the result high H2O2 levels. Against this background, CRBN-regulated proteins such as CD147 and MCT1 as well as TrxR may serve as new therapeutic target structures while functional read-outs as CD147 and MCT1 destabilization or antioxidative capacity may serve as predictive biomarkers for IMiD response. 1. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science . 2010;327(5971):1345- 1350. 2. Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood . 2011;118(18):4771-4779. 3. Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia . 2012;26(11):2326-2335. 4. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science . 2014;343(6168):301-305. 5. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science . 2014;343(6168):305-309. 6. Gandhi AK, Kang J, Havens CG, et al. 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.). Br J Haematol . 2014;164(6):811-821. 7. Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood . 2014;124(4):536-545. 8. Kronke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature . 2015;523(7559):183-188. 9. Eichner R, Heider M, Fernandez-Saiz V, et al. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat Med . 2016;22(7):735-743. 10. Sebastian S, Zhu YX, Braggio E, et al. Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity. Blood . 2017;129(8):991-1007. Disclosures Bassermann: Celgene: Research Funding.

scholarly journals IKZF1/3 and CRL4CRBN E3 ubiquitin ligase mutations and resistance to immunomodulatory drugs in multiple myeloma

Haematologica ◽  
2019 ◽  
Vol 105 (5) ◽  
pp. e237-e241 ◽  
Author(s):  
Santiago Barrio ◽  
Umair Munawar ◽  
Yuan Xiao Zhu ◽  
Nicola Giesen ◽  
Chang-Xin Shi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Immunomodulatory Drugs

Proteolysis-targeting chimeras mediate the degradation of bromodomain and extra-terminal domain proteins

2020 ◽  
Vol 12 (18) ◽  
pp. 1669-1683
Author(s):  
Yifei Yang ◽  
Zhenwei Wu ◽  
Pan Chen ◽  
Peiyuan Zheng ◽  
Huibin Zhang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Drug Discovery And Development ◽  
Terminal Domain ◽  
Super Enhancer ◽  
Bet Inhibitors ◽  
Subsequent Degradation ◽  
Bet Protein

Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been involved with several types of cancers as a candidate. Up to now, there are 16 pan-BET inhibitors in clinical trials, however, most of them have undesirable off-target and side-effects. The proteolysis-targeting chimeras technology through a heterobifunctional molecule to link the target protein and E3 ubiquitin ligase, causes the target’s ubiquitination and subsequent degradation. By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimeras.

scholarly journals An IMiD-induced SALL4 degron system for selective degradation of target proteins

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Satoshi Yamanaka ◽  
Yuki Shoya ◽  
Saya Matsuoka ◽  
Hisayo Nishida-Fukuda ◽  
Norio Shibata ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Living Cells ◽  
Cellular Biology ◽  
Immunomodulatory Drugs ◽  
Unknown Mechanism ◽  
Selective Degradation ◽  
Ubiquitin Ligase Complex ◽  
Powerful Approach

AbstractRegulating the amount of proteins in living cells is a powerful approach for understanding the functions of the proteins. Immunomodulatory drugs (IMiDs) induce the degradation of neosubstrates by interacting with celebron (CRBN) in the cullin E3 ubiquitin ligase complex (CRL4CRBN). Here, we developed the IMiD-dependent Sal-like protein 4 (SALL4) degron (S4D) system for chemical protein knockdown. In transient assays, an N- or C-terminal S4D tag induced the degradation of proteins localized to various subcellular compartments, including the plasma membrane. The activity of luciferase-S4D was reduced by 90% within 3 h of IMiD treatment. IMiD treatment reduced the expression of endogenous S4D-fused RelA and IκBα in knock-in (KI) experiments. Interestingly, the IκBα knockdown suggested that there may be another, unknown mechanism for RelA translocation to the nucleus. Furthermore, 5-hydroxythalidomide as a thalidomide metabolite specifically degradated S4D-tagged protein. These results indicate that the S4D system is a useful tool for cellular biology.

scholarly journals A Novel Degron-mediated Degradation of the RTG Pathway Regulator, Mks1p, by SCFGrr1

2005 ◽  
Vol 16 (10) ◽  
pp. 4893-4904 ◽  
Author(s):  
Zhengchang Liu ◽  
Mário Spírek ◽  
Janet Thornton ◽  
Ronald A. Butow
Keyword(s):  
Transcription Factors ◽  
Ubiquitin Ligase ◽  
Positive Charge ◽  
E3 Ubiquitin Ligase ◽  
Retrograde Signaling ◽  
Yeast Cells ◽  
Leucine Rich Repeat ◽  
Negative Regulators ◽  
Acidic Domain ◽  
Lrr Domain

Yeast cells respond to mitochondrial dysfunction by altering the expression of a subset of nuclear genes, a process known as retrograde signaling (RS). RS terminates with two transcription factors, Rtg1p and Rtg3p. One positive regulator, Rtg2p, and four negative regulators, Lst8p, Mks1p, and the redundant 14-3-3 proteins, Bmh1p and Bmh2p, control RS upstream of Rtg1/3p. Mks1p is negatively regulated by binding to Rtg2p and positively regulated when bound to Bmh1/2p. Here we report that Grr1p, a component of the SCFGrr1 E3 ubiquitin ligase, modulates RS by affecting Mks1p levels. Grr1p polyubiquitinates Mks1p not bound to either Rtg2p or to Bmh1/2p, targeting it for degradation. An acidic domain region of Mks1p constitutes the portable Mks1p degron sequence. We have isolated dominant mutations in Grr1p leading to increased Mks1p degradation. These mutations result in a gain of positive charge on the concave surface of the leucine rich repeat (LRR) domain of Grr1p, the proposed substrate binding site. We propose that Mks1p is a central player of RS and is acted upon by multiple regulators of the pathway.

scholarly journals The Human Adenovirus Type 5 E4orf6/E1B55K E3 Ubiquitin Ligase Complex Can Mimic E1A Effects on E2F

mSphere ◽  
2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Frédéric Dallaire ◽  
Sabrina Schreiner ◽  
G. Eric Blair ◽  
Thomas Dobner ◽  
Philip E. Branton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Synthesis ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Viral Gene Expression ◽  
Adenovirus Vector ◽  
Human Adenovirus ◽  
Viral Gene ◽  
E2f Transcription Factors

ABSTRACT During the course of work on the adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins, we found, very surprisingly, that expression of these species was sufficient to permit low levels of replication of an adenovirus vector lacking E1A, the central regulator of infection. E1A products uncouple E2F transcription factors from Rb repression complexes, thus stimulating viral gene expression and cell and viral DNA synthesis. We found that the E4orf6/E1B55K ligase mimics these functions. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication. The human adenovirus E4orf6/E1B55K E3 ubiquitin ligase is well known to promote viral replication by degrading an increasing number of cellular proteins that inhibit the efficient production of viral progeny. We report here a new function of the adenovirus 5 (Ad5) viral ligase complex that, although at lower levels, mimics effects of E1A products on E2F transcription factors. When expressed in the absence of E1A, the E4orf6 protein in complex with E1B55K binds E2F, disrupts E2F/retinoblastoma protein (Rb) complexes, and induces hyperphosphorylation of Rb, leading to induction of viral and cellular DNA synthesis as well as stimulation of early and late viral gene expression and production of viral progeny of E1/E3-defective adenovirus vectors. These new and previously undescribed functions of the E4orf6/E1B55K E3 ubiquitin ligase could play an important role in promoting the replication of wild-type viruses. IMPORTANCE During the course of work on the adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins, we found, very surprisingly, that expression of these species was sufficient to permit low levels of replication of an adenovirus vector lacking E1A, the central regulator of infection. E1A products uncouple E2F transcription factors from Rb repression complexes, thus stimulating viral gene expression and cell and viral DNA synthesis. We found that the E4orf6/E1B55K ligase mimics these functions. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication.

scholarly journals Functions of COP1/SPA E3 Ubiquitin Ligase Mediated by MpCRY in the Liverwort Marchantia Polymorpha under Blue Light

2021 ◽  
Vol 23 (1) ◽  
pp. 158
Author(s):  
Li Zhang ◽  
Tianhong Li ◽  
Shengzhong Su ◽  
Hao Peng ◽  
Sudi Li ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Blue Light ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Land Plants ◽  
Marchantia Polymorpha ◽  
Regulatory Pathway ◽  
Knock Out

COP1/SPA1 complex in Arabidopsis inhibits photomorphogenesis through the ubiquitination of multiple photo-responsive transcription factors in darkness, but such inhibiting function of COP1/SPA1 complex would be suppressed by cryptochromes in blue light. Extensive studies have been conducted on these mechanisms in Arabidopsis whereas little attention has been focused on whether another branch of land plants bryophyte utilizes this blue-light regulatory pathway. To study this problem, we conducted a study in the liverwort Marchantia polymorpha and obtained a MpSPA knock-out mutant, in which Mpspa exhibits the phenotype of an increased percentage of individuals with asymmetrical thallus growth, similar to MpCRY knock-out mutant. We also verified interactions of MpSPA with MpCRY (in a blue light-independent way) and with MpCOP1. Concomitantly, both MpSPA and MpCOP1 could interact with MpHY5, and MpSPA can promote MpCOP1 to ubiquitinate MpHY5 but MpCRY does not regulate the ubiquitination of MpHY5 by MpCOP1/MpSPA complex. These data suggest that COP1/SPA ubiquitinating HY5 is conserved in Marchantia polymorpha, but dissimilar to CRY in Arabidopsis, MpCRY is not an inhibitor of this process under blue light.

scholarly journals Targeting oncoproteins with a positive selection assay for protein degraders

2021 ◽  
Vol 7 (6) ◽  
pp. eabd6263
Author(s):  
Vidyasagar Koduri ◽  
Leslie Duplaquet ◽  
Benjamin L. Lampson ◽  
Adam C. Wang ◽  
Amin H. Sabet ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Small Molecules ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Signal To Noise ◽  
Independent Manner ◽  
Intracellular Proteins ◽  
Oncogenic Transcription Factor

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal (“down”) assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal (“up”) assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9–based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.

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