Molecule Information

General Information of the Molecule (ID: Mol00304)

• Name: Protein cereblon (CRBN) ,Homo sapiens
• Synonyms: AD-006
• Molecule Type: Protein
• Gene Name: CRBN
• Gene ID: 51185
• Location: chr3:3144628-3179727[-]
• Sequence:
  MAGEGDQQDAAHNMGNHLPLLPAESEEEDEMEVEDQDSKEAKKPNIINFDTSLPTSHTYL
  GADMEEFHGRTLHDDDSCQVIPVLPQVMMILIPGQTLPLQLFHPQEVSMVRNLIQKDRTF
  AVLAYSNVQEREAQFGTTAEIYAYREEQDFGIEIVKVKAIGRQRFKVLELRTQSDGIQQA
  KVQILPECVLPSTMSAVQLESLNKCQIFPSKPVSREDQCSYKWWQKYQKRKFHCANLTSW
  PRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPSNPIDFSYRVAACLPIDDVLRIQLLK
  IGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETL
  TVYKACNLNLIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTATKKDMSPQKFWGLTRS
  ALLPTIPDTEDEISPDKVILCL
• 3D-structure: PDB ID: 9CUO; Classification: Ligase; Method: X-ray diffraction; Resolution: 1.60 Å
• Function: Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2 or ILF2. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. Maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons. Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1. May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism.
• Uniprot ID: CRBN_HUMAN
• Ensembl ID: ENSG00000113851
• HGNC ID: HGNC:30185

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Lenalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Lenalidomide
• Molecule Alteration: Truncating mutation; p.Q99*
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Pomalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Mechanism Description: Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma.

Disease Class: Epstein-barr virus (ebv) infection [ICD-11: XN0R2] [3]

• Resistant Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Myeloproliferative neoplasm [ICD-11: 2A22.0] [4]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Nonsense; p.Q100* (c.298C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nonsense p.Q100* (c.298C>T) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway.

Disease Class: Myeloproliferative neoplasm [ICD-11: 2A22.0] [4]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Missense mutation; p.R283K (c.848G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.R283K (c.848G>A) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway

Thalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1], [4]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Thalidomide
• Molecule Alteration: Truncating mutation; p.R283K
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/RAS signaling pathway; Regulation; N.A.
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
• Experiment for Drug Resistance: Longitudinal copy number aberration (CNA) analysis
• Mechanism Description: Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Multiple myeloma [ICD-11: 2A83]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.90E-05; Fold-change: 1.10E+00; Z-score: 3.07E+00
• The Studied Tissue: Peripheral blood
• The Specified Disease: Multiple myeloma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.78E-01; Fold-change: 1.91E-01; Z-score: 2.13E-01

References

• Ref 1: Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016 Sep 29;128(13):1735-44. doi: 10.1182/blood-2016-06-723007. Epub 2016 Aug 11.
• Ref 2: Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma .Blood. 2021 Jan 14;137(2):232-237. doi: 10.1182/blood.2020007081. 10.1182/blood.2020007081
• Ref 3: Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas. Sci Rep. 2023 Jul 18;13(1):11596.
• Ref 4: Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Br J Haematol. 2013 Jun;161(5):748-51. doi: 10.1111/bjh.12291. Epub 2013 Mar 11.