Table 1. Table describing the key MCL biomarkers that inform diagnosis, prognosis, and functional drug interactions of MCL, along with their normal functions.
| Major Family | Biomarker | Class | Normal Function | Expression in MCL | Involved Pathway(s) | Interaction with MCL Drugs | Detection Technique | References |
|---|---|---|---|---|---|---|---|---|
| Cell-Cycle Regulation related markers | Cyclin D1 | Protein | Regulator of CDK4 and CDK6 | Up-Regulated | Cell Cycle | PD0332991 and others inhibit CDKs | IHC, PCR, FISH | 215, 216 |
| Ki67 | Protein | Necessary for cell proliferation and RNA transcription | Up-Regulated | Cell Cycle | COX 2 and CDK inhibitors decrease Ki67 | IHC, PCR, FISH | 134, 216, 217 | |
| ATM | Protein Kinase | Induces cell cycle arrest, DNA repair, apoptosis | Down-Regulated | Homologous Recombination Repair and Cell Cycle regulation | KU 55933, KU-60019 and VE-821 inhibit ATM | IHC, PCR, FISH | 216, 218 | |
| CHK2 | Protein | Tumor suppressor, regulates cell division | Down-Regulated | CDK-mediated phosphorylation and removal of Cdc6 | AZD7762, CCT241533 hydrochloride and NSC 109555 ditosylate inhibit CHK2 | IHC, PCR, FISH | 216, 219 | |
| CDK4 | Gene | Catalyzes cell cycle G1 phase progression | Up-Regulated | Cell cycle regulation, especially CDK-mediated phosphorylation and removal of Cdc6 | AZD-5438, Purvalanol A and Purvalanol B inhibit CDK's | IHC, PCR, FISH | 216, 218 | |
| RAN | Protein | Required for importing of proteins into nucleus as well as transporting RNA out of the nucleus. Involved in chromatin condensation and cell cycle regulation. | Up-Regulated | Regulation of nucleocytoplasmic transportation and mitotic spindle formation by forming CRM1/RAN GTP complex with Chromosomal region maintenance 1 (CRM1) | CRM1 inhibitors LMB (Leptomycin B and other LMB analogues) indirectly inhibit RAN | IHC, PCR, FISH | 216, 220 | |
| MYC | Protein | Controls DNA replication, causes B cell proliferation, regulates cell growth and apoptosis | Up-Regulated | ERK Signaling, PEDF Induced Signaling, ErbB signaling pathway | Covalent inhibitor of cyclin dependent kinase 7 (CDK7) inhibit MYC | IHC, PCR, FISH | 216, 221 | |
| TCL1A | Onco protein | T cell leukemia/lymphoma 1A promotes nuclear translocation of AKT1, enhances cell proliferation, promotes cell survival; interferes with NF-kB inhibitor IκB | Up-Regulated | P13K-Akt signaling where TLC1A acts as a co-activator of AKT | Rapamycin inhibits Tcl1/Akt/mTOR pathway | IHC, PCR, FISH | 85, 216, 222 | |
| p27 | Gene | Inhibits CDK2 and CDK4, involved in G1 phase arrest | Down-Regulated | Cell cycle inhibitors and regulators | NSAIDS increase expression of p27 | IHC, PCR, FISH | 216, 223 | |
| CHK1 | Protein | CDK-mediated phosphorylation and removal of Cdc6, G2/M Checkpoints, | Down-Regulated | Coordinates response to DNA damage during cell cycle and regulates checkpoint in cell cycle | CHK1 inhibitor PF-00477736 works synergistically with Wee1 inhibitor (MK-1775) to induce apoptosis in MCL cell lines | IHC, PCR, FISH | 216, 224 | |
| BAFF-R | Gene | Enhances B-cell survival, regulates B-cell population | Up-Regulated | PEDF Induced Signaling, TNF, Akt and TGF-Beta Pathway | anti-BAFF antibody has therapeutic application against SLE but has not been tested against MCL | IHC, PCR, FISH | 216, 225 | |
| Transcription Regulators | Sox11 | Trans-cription factor | Plays role in determining cell fate | Up-Regulated | Notch, ERK Signaling | methylation of SOX11 promotor region reduces expression of SOX11 | IHC, PCR, FISH | 2, 48, 216 |
| STAT3 | Protein | Transcription activator | Up-Regulated | growth factors, cytokines and interleukin signaling pathways | WP1066 with vorinostat has been tested against MCL. Other STAT-3 inhibitors are also available | IHC, PCR, FISH | 216, 226, 227 | |
| Nuclear Factor Kappa Beta | Protein | Controls DNA transcription, cytokine production, and cell survival | Up-Regulated | NFKB signaling pathway | proteasome inhibitor PS-341 or a specific pIκBα inhibitor, BAY 11-7082 have been used against MCL cell lines | IHC, PCR, FISH | 216, 228 | |
| Tumor Suppression/Necr-osis related markers | Tp53 | Gene | Codes for tumor suppressor protein p53 | Up-Regulated | apoptosis and cell cycle related signaling pathways | Cyclic Pifithrin-alpha hydrobromide and CP 31398 dihydrochloride stabilizes p53 | IHC, PCR, FISH | 61, 62, 216 |
| INK4A | Protein Kinase | Tumor suppressor, slows down cell cycle | Mutated or Deleted | Cellular Senescence and Cell Cycle Regulation | HDAC inhibitors interact with INK4A to regulate the cell proliferation | IHC, PCR, FISH | 133, 216 | |
| RB1 | Gene | Regulator of entry into cell division, tumor suppressor | Inactivated | CDK-mediated phosphorylation and removal of Cdc6, Cell Cycle Regulation | HDAC inhibitors increase RB1 expression in Myeloid-derived suppressor cells | IHC, PCR, FISH | 216, 229 | |
| MDM2 | Protein | Mediates ubiquitination of p53 | Up-Regulated | PI-3K cascade signaling, CDK-mediated phosphorylation and removal of Cdc6 | AMG232, JNJ-26854165 and Nutlin-3 inhibits MDM2-p53 interaction | IHC, PCR, FISH | 216, 230 | |
| BCL-6 | Gene | Transcriptional suppressor, suppresses genes related to differentiation, cell cycle, and apoptosis | Down-Regulated | IL4-mediated signaling events, B Cell Receptor, Fox O signaling pathways, Direct p53 effectors | Rituximab inhibits BCL66 Paraffin targets BCL-6 | IHC, PCR, FISH | 216, 231 | |
| BCL-2 | Protein | Regulator of apoptosis | Up-Regulated | PEDF Induced Signaling, TGF-Beta, ERK Signaling, | 2,3-DCPE hydrochloride, ABT-199, ABT-263, ABT-737 and Apogossypolone inhibit BCL-2 | IHC, PCR, FISH | 216, 232 | |
| BIRC3 (Baculoviral IAP Repeat Containing 3) | Protein | Anti-apoptotic protein regulates caspases and apoptosis, modulates inflammatory signaling and immunity | Mutated or Deleted | apoptosis and NFKB signaling pathway | Needs further research | IHC, PCR, FISH | 216, 233 | |
| PTEN (Phosphatase and tensin homolog) | Gene | Tumor suppressor | Mutated or Deleted | PI-3K cascade Signaling Pathway | several drugs under clinical investigation | IHC, PCR, FISH | 216, 234 | |
| TNFAIP/A20 | Protein | A20-binding inhibitor of NF-κB | Mutated or Deleted | Akt, ERK, NFKB Signaling Pathways | Overexpression of ABINs inhibits NF-κB activation; needs further research | IHC, PCR, FISH | 216, 235 | |
| TNFRSF10B | Gene | Tumor Necrosis factor receptor, Transduces apoptosis signals, | Inactivated | Death Receptor, TNF, Akt and TGF-Beta signaling Pathway | Cisplatin is known to alter expression of TNFRSF10B | IHC, PCR, FISH | 216, 236 | |
| Apoptosis-Related markers | repp86 | Protein | Spindle assembly factor, required for assembly of microtubules during apoptosis, | Up-Regulated | Cell Cycle Checkpoint control, Aurora A, PLK1 signaling events, Cell cycle spindle assembly and chromosome separation | Not available | IHC, PCR, FISH | 216, 237 |
| survivin | Protein | Inhibitor of Apoptosis, Regulates mitosis | Up-regulated | Cell cycle and IL-23 immune response pathway | Not available | IHC, PCR, FISH | 216, 238 | |
| FAF1 | Protein | Mediates programmed cell death | Deleted | Apoptosis, TNF-alpha/NF-kB Signaling Pathway, Apoptosis and Autophagy | Not available | IHC, PCR, FISH | 216, 239 | |
| RNA/DNA Repair Regulator related markers | POLE2 | Protein | DNA binding, Protein Binding, DNA-directed DNA polymerase activity | Up-Regulated | Telomere C-Strand Synthesis, CDK-mediated phosphorylation and removal of Cdc6, DNA Repair, Mitotic G1-G1/S phases | Thioguanine Daunorubicin and Cytosine arabinoside targets POLE2 | IHC, PCR, whole-genome and/or whole-exome sequencing | 216, 236 |
| Topoisomerase Iiα | Protein | Cut strands of DNA to manage DNA tangles and supercoils, promotes chromosomal disentanglement | Up-Regulated | Cell Cycle, Chromatin regulation/acetylation | HU-331, ICRF-187/193, mitindomide and m-AMSA inhibits topoisomerase Iiα | IHC, PCR, whole-genome and/or whole-exome sequencing | 216, 240 | |
| IGF2BP2 | Gene | RNA-binding factor, facilitates mRNA transport and storage | Up-Regulated | Binding of RNA by Insulin-like growth factor-2 mRNA binding proteins | Not available | IHC, PCR, whole-genome and/or whole-exome sequencing | 216, 241 |
Please see Supplementary Table 1 access complete table.