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| Description | 462 amino acids - 5 functional domains A/B (transcriptional regulation), C (DNA binding domain, contains 2 zinc fingers), D (cellular localization signal), E (ligand-binding domain) and F (function?) |
| Expression | in hematopoietic cells |
| Localisation | nuclear |
| Function | ligand-dependent transcription factor specifically involved in hematopoietic cells differentiation and maturation = receptor for all-trans retinoic acid (ATRA) and 9-cis RA which are intracellular metabolites of vitamine A, active in cellular differentiation and morphogenesis after linking with ATRA, RARA binds with a high affinity as a heterodimer with RXR (retinoid X receptor protein) to the RARE domain (retinoic acid response elements), a DNA sequence common to a number of genes and located in their promoter the gene response to RARA binding is modulated by a series of co-repressors and co-activators |
| Homology | with RARB and RARG (retinoic acid receptors ? and ?), 9-cis RA receptors (RXRs) and receptors for thyroid and steroid hormones and for vitamine D3 |
| Entity | t(15;17)(q24;q21) / acute promyelocytic leukemia (APL) -->PML - RARA |
| Disease | typical APL (or M3 ANLL, FAB classification), approximately 98% of APL cases; abnormal promyelocytes with Auer rods and bundles (faggots); disruption of the PODs with a microspeckeled pattern; maturation response to all-trans retinoic acid (ATRA) therapy |
| Prognosis | immediate prognosis impaired by intravascular disseminated coagulopathy; long term prognosis is favorable with treatment combining ATRA plus chemotherapy |
| Cytogenetics | variant or complex t(15;17) translocation in 5% of cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), del(9q), ider(17)t(15;17), +21 |
| Hybrid/Mutated Gene | the crucial fusion transcript is 5'PML-3'RARA, encoded by der(15) chromosome; the counterpart 5'RARA-3'PML encoded by der(17) is inconstant breakpoint in RARA gene is always located in intron between A and B domains three breakpoint clusters in PML gene: bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), giving rise respectively to the long (L), intermediate (V) and short (S) length hybrid PML-RARAtranscripts; V form would be linked to ATRA decreased sensitivity and S form to association with an excess of secondary chromosome changes. |
| Abnormal Protein | 106 Kda fusion protein; role in the leukemogenic process by probable interference with the signalling pathway leading to differentiation and maturation of myeloid precursors (mainly dysregulation of retinoid-inducible genes involved in myeloid differentiation) |
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| Entity | t(11;17)(q23;q12) / acute promyelocytic leukemia -->PLZF-RARA |
| Disease | variant acute promyelocytic leukemia (APL) form with atypical cytologic aspects (intermediate morphology between M2 and M3, no Auer rods) and no response to ATRA therapy; less than 1% of APL cases. |
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| Entity | t(5;17)(q35;q12) / acute promyelocytic leukemia --> NPM-RARA |
| Disease | exceptional; probable response to ATRA |
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| Entity | t(11;17)(q13;q12) / acute promyelocytic leukemia --> NuMA-RARA |
| Disease | exceptional: probable response to ATRA |
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| Entity | t(11;17)(q23;q12) / M5 acute non lymphocytic leukemia --> MLL-RARA |
| Disease | 1 case to date; not to be confused with the t(11;17)(q23;q12) mentioned above; not found in APL; belongs to the MLL/11q23 leukemias |
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| The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. |
| de Thˆ© H, Chomienne C, Lanotte M, Degos L, Dejean A |
| Nature. 1990 ; 347 (6293) : 558-561. |
| PMID 2170850 |
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| Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. |
| Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM |
| Cell. 1991 ; 66 (4) : 663-674. |
| PMID 1652368 |
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| Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation. |
| Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F, Avvisati G, Pelicci PG, Jetten AM |
| Cancer research. 1992 ; 52 (13) : 3687-3692. |
| PMID 1319828 |
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| Genetics of APL and the molecular basis of retinoic acid treatment. |
| Casini T, Grignani F, Pelicci PG |
| International journal of cancer. Journal international du cancer. 1997 ; 70 (4) : 473-474. |
| PMID 9033658 |
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| The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. |
| Grimwade D |
| British journal of haematology. 1999 ; 106 (3) : 591-613. |
| PMID 10468848 |
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| Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. |
| Melnick A, Licht JD |
| Blood. 1999 ; 93 (10) : 3167-3215. |
| PMID 10233871 |
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