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==Cancer Category/Type==
==Cancer Category/Type==
Based on the early French-American-British (FAB) classification, acute promyelocytic leukaemia (APL) is one of the subtypes (M3) of acute myeloid leukemia AML [1].
Based on the early French-American-British (FAB) classification, Acute Promyelocytic Leukaemia (APL) is one of the subtypes (M3) of Acute Myeloid Leukemia AML [1].
[http://www.ccga.io/index.php/Acute_Promyelocytic_Leukemia_(APL)_with_PML-RARA Acute Promyelocytic Leukemia (APL) with PML-RARA]
[http://www.ccga.io/index.php/Acute_Promyelocytic_Leukemia_(APL)_with_PML-RARA Acute Promyelocytic Leukemia (APL) with PML-RARA]
[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
The PML-RARA fusion is reported to be found in 5-15% of AML, may occur at any age, but predominantly in adult in mid-life [1, 2]. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of ATRA or arsenic trioxide [3].
The PML-RARA fusion is reported to be found in 5-15% of AML, may occur at any age, but predominantly in adult in mid-life [1, 2]. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of all-trans retinoic acid (ATRA) or arsenic trioxide [3].
==Gene Overview==
==Gene Overview==
The RARA gene encodes one of the three main receptor subclasses for retinoic acid. Retinoic acid receptors bind as heterodimers to their target DNA when bound to their ligand (retinoic acid) and regulate gene expression in various biological processes including hematopoiesis. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5-AGGTCA-3 sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation ([https://www.uniprot.org/uniprot/P10276#function adapted from Uniprot description]).
The RARA gene encodes one of the three main receptor subclasses for retinoic acid. Retinoic acid receptors bind as heterodimers to their target DNA when bound to their ligand (retinoic acid) and regulate gene expression in various biological processes including hematopoiesis. The RXR/RAR heterodimers bind to the DNA retinoic acid response elements (RARE). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. Upon ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation of target genes ([https://www.uniprot.org/uniprot/P10276#function adapted from Uniprot description]).
It is likely that the fusion genes with RARA can both activate normally inactive genes and repress normally active genes.
Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia AML that is almost entirely caused by the t(15;17)q22;q11) translocation resulting in the PML-RARA fusion gene. It is likely that the fusion genes with RARA can both activate normally inactive genes and repress normally active genes. The Pml-Rara fusion protein interferes with the binding of the ligand retinoic acid with the normal retinoic acid receptor, thus converting the retinoic acid receptor into a transcriptional activator, ultimately resulting in the inhibition of gene expression for hematopoietic differentiation and the maturation arrest of hematopoietic progenitors at the promyelocyte stage. In addition, the Pml-Rara protein acts as a dominant repressor of the normal PML protein [2].
==Common Alteration Types==
==Common Alteration Types==
The translocation involving PML and RARA are found in more than 90% of cases of APL. Other fusion partners to RARA found in APL include PZLF, NPM, NuMA, STAT5b and BCOR. These rarer fusion genes account for around 5% of the total found in APL. Patients with these different fusion genes show different clinical responses to ATRA treatment. PZLF-RARA and STAT5b-RARA cases were refractory to ATRA, whereas NPM-RARA and NuMA-RARA were reported to be responsive. BCOR-RARA was also responsive to ATRA but carries a higher risk of relapse [4]
The translocation involving PML and RARA are found in more than 90% of cases of APL. Other fusion partners to RARA found in APL include PZLF, NPM1, NUMA1, STAT5B and BCOR. These rarer fusion genes account for around 5% of the total found in APL. Patients with these different fusion genes show different clinical responses to ATRA treatment. PZLF-RARA and STAT5b-RARA cases were refractory to ATRA, whereas NPM-RARA and NuMA-RARA were reported to be responsive. BCOR-RARA was also responsive to ATRA but carries a higher risk of relapse [4]
{| class="wikitable sortable"
{| class="wikitable sortable"
! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion
! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion
|-
|-
| EXAMPLE: X ||EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X
| || || || X || || X
|}
|}
[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
[http://www.ccga.io/index.php/NPM1 NPM1]
[http://www.ccga.io/index.php/PML PML]
==External Links==
==External Links==