Comparison of N-Protein/RAR Fusion Products
| . | PML-RARα . | PLZF-RARα . | NPM-RARα . | NuMA-RARα . |
|---|---|---|---|---|
| Breakpoint variants | Three breakpoint clusters result in three major forms265-271 | Most cases include first two Zn fingers358,359 361 | Two fusion cDNAs alternative splicing505 | Only one breakpoint509 |
| N-protein structures | All variants contain: RING, B-box, coiled-coil270 271 | POZ/BTB, first two Zn fingers358,359 361 | Oligomerization domain, metal binding domain and first acidic domain505 | N-terminal globular domain and central coiled region548 |
| Nuclear localization | Localizes to ∼100 microspeckles, which are distinct from NBs. May also localize in the cytoplasm173,197 198 | Localized to microspeckles, not to nuclear bodies nor cytoplasm216,299 414 | Microspeckled pattern384 | Sheetlike aggregates548 |
| Homodimerization | Through coiled-coil domain171 287 | Through the POZ/BTB domain289 383 | Presumably through oligomerization domain | Presumably through NuMA coiled domain |
| Heterologous interactions | PML, RXR, SMRT, N-Cor, HDAC1171,287,289,295,296 299 | PLZF, RXR, SMRT, N-Cor, HDAC1, sin3A289,294-296,299 383 | Unknown. Possible interaction with RXR | Unknown. Possible interaction with RXR |
| Transcriptional effects | Dominant negative for retinoids. Avid binding to corepressors, relieved only by high dose ATRA.13,15,157,292,294-296 299 | Dominant negative for retinoids. Avid binding to corepressors, not relieved by high-dose ATRA289,294-296,299,383,398 408 | ATRA-dependent transactivation419 | Unknown |
| ATRA sensitivity | Sensitive to ATRA302,304-306 308 | Generally insensitive to ATRA as a single agent,361 may respond to combination therapy363 366 | Sensitive to ATRA384,418 505 | Sensitive to ATRA509 |
| Effects of ATRA | Relocalizes PML to NBs, degrades PML-RARα, upregulates RARα, differentiation13,15,94-96,157,173,191,197,198,290,292,310-312,324,327,336 | ATRA + HDAC inhibitor suppress growth and promote differentiation,299 336 degrades PLZF-RARα414 | Induces differentiation and inhibits growth336 505 | Not yet reported |
| Effects of arsenic | Induces CR in APL, rapid degradation of PML-RARα and apoptosis311,315-317 320 | Fails to degrade PLZF-RARα or induce apoptosis414 | Not yet reported | Not yet reported |
| Transfected cell models | Inhibits differentiation, protects from apoptosis, enhances proliferation, does not transform cells300,324,327 336 | Blocks differentiation, fails to increase sensitivity to ATRA, murine marrow progenitors could be serially passaged336 349 | Blocked differentiation and enhanced proliferation336 507 | Not yet reported |
| Transgenic models | Several models. Closest to human APL is MRP8 promoter construct339-342 345 | Mice develop CML like syndrome earlier than PML-RAR. Poor response to ATRA299 508 | APL sensitive to ATRA508 | Not yet reported |
| Miscellaneous | Resistance to ATRA caused by mutations in ligand-binding domain306-309 603 | May bind to different RAREs compared with PML-RARα383 | Does not localize to NB, does not delocalize PML but does delocalize PLZF234 384 | Does not localize to NB, does not delocalize PML548 |
| Model | Multimerization, sequestration of RXR and other factors. Increased affinity for corepressors. Transcriptional effects on target genes. Interference with PLZF actions. | Multimerization, sequestration of RXR and other factors. Increased affinity for corepressors. Transcriptional effects on target genes. Reciprocal fusion may play a role. | Multimerization, sequestration of RXR and other factors. Transcriptional effects on target genes. Interference with PLZF actions. | Multimerization, sequestration of RXR and other factors. Interference with apoptotis program. |
| Reciprocal translocation | Present in 70% to 80% of cases. Unclear role in leukemogenesis351 352 | Present in all cases tested. Activates PLZF target genes and induces cell proliferation5,289,394,395,406 604 | Identified in the index case. Actions still unknown419 | Not yet reported |
| . | PML-RARα . | PLZF-RARα . | NPM-RARα . | NuMA-RARα . |
|---|---|---|---|---|
| Breakpoint variants | Three breakpoint clusters result in three major forms265-271 | Most cases include first two Zn fingers358,359 361 | Two fusion cDNAs alternative splicing505 | Only one breakpoint509 |
| N-protein structures | All variants contain: RING, B-box, coiled-coil270 271 | POZ/BTB, first two Zn fingers358,359 361 | Oligomerization domain, metal binding domain and first acidic domain505 | N-terminal globular domain and central coiled region548 |
| Nuclear localization | Localizes to ∼100 microspeckles, which are distinct from NBs. May also localize in the cytoplasm173,197 198 | Localized to microspeckles, not to nuclear bodies nor cytoplasm216,299 414 | Microspeckled pattern384 | Sheetlike aggregates548 |
| Homodimerization | Through coiled-coil domain171 287 | Through the POZ/BTB domain289 383 | Presumably through oligomerization domain | Presumably through NuMA coiled domain |
| Heterologous interactions | PML, RXR, SMRT, N-Cor, HDAC1171,287,289,295,296 299 | PLZF, RXR, SMRT, N-Cor, HDAC1, sin3A289,294-296,299 383 | Unknown. Possible interaction with RXR | Unknown. Possible interaction with RXR |
| Transcriptional effects | Dominant negative for retinoids. Avid binding to corepressors, relieved only by high dose ATRA.13,15,157,292,294-296 299 | Dominant negative for retinoids. Avid binding to corepressors, not relieved by high-dose ATRA289,294-296,299,383,398 408 | ATRA-dependent transactivation419 | Unknown |
| ATRA sensitivity | Sensitive to ATRA302,304-306 308 | Generally insensitive to ATRA as a single agent,361 may respond to combination therapy363 366 | Sensitive to ATRA384,418 505 | Sensitive to ATRA509 |
| Effects of ATRA | Relocalizes PML to NBs, degrades PML-RARα, upregulates RARα, differentiation13,15,94-96,157,173,191,197,198,290,292,310-312,324,327,336 | ATRA + HDAC inhibitor suppress growth and promote differentiation,299 336 degrades PLZF-RARα414 | Induces differentiation and inhibits growth336 505 | Not yet reported |
| Effects of arsenic | Induces CR in APL, rapid degradation of PML-RARα and apoptosis311,315-317 320 | Fails to degrade PLZF-RARα or induce apoptosis414 | Not yet reported | Not yet reported |
| Transfected cell models | Inhibits differentiation, protects from apoptosis, enhances proliferation, does not transform cells300,324,327 336 | Blocks differentiation, fails to increase sensitivity to ATRA, murine marrow progenitors could be serially passaged336 349 | Blocked differentiation and enhanced proliferation336 507 | Not yet reported |
| Transgenic models | Several models. Closest to human APL is MRP8 promoter construct339-342 345 | Mice develop CML like syndrome earlier than PML-RAR. Poor response to ATRA299 508 | APL sensitive to ATRA508 | Not yet reported |
| Miscellaneous | Resistance to ATRA caused by mutations in ligand-binding domain306-309 603 | May bind to different RAREs compared with PML-RARα383 | Does not localize to NB, does not delocalize PML but does delocalize PLZF234 384 | Does not localize to NB, does not delocalize PML548 |
| Model | Multimerization, sequestration of RXR and other factors. Increased affinity for corepressors. Transcriptional effects on target genes. Interference with PLZF actions. | Multimerization, sequestration of RXR and other factors. Increased affinity for corepressors. Transcriptional effects on target genes. Reciprocal fusion may play a role. | Multimerization, sequestration of RXR and other factors. Transcriptional effects on target genes. Interference with PLZF actions. | Multimerization, sequestration of RXR and other factors. Interference with apoptotis program. |
| Reciprocal translocation | Present in 70% to 80% of cases. Unclear role in leukemogenesis351 352 | Present in all cases tested. Activates PLZF target genes and induces cell proliferation5,289,394,395,406 604 | Identified in the index case. Actions still unknown419 | Not yet reported |