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==Cancer Category/Type==
==Cancer Category/Type==
[http://www.ccga.io/index.php/HAEM4:Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
[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/HAEM5:Acute_promyelocytic_leukaemia_with_PML::RARA_fusion Acute Promyelocytic Leukemia (APL) with PML-RARA]
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]. The PML-RARA fusion is reportedly found in 5-15% of AML and occurs at any age but predominantly in adults in mid-life [1,2]. ''RARA'' fusion proteins behave as potent transcriptional repressors of retinoic acid signaling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of all-trans retinoic acid (ATRA) or arsenic trioxide [1-5]. ATO (arsenic trioxide) also induces differentiation of the malignant myeloid clone by dissociating the PML/RAR-alpha-RXR complex from the target genes and was found to have a synergistic action with ATRA [5].
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 [1, 2, 3, 4].
ATO (arsenic trioxide) also induces differentiation of the malignant myeloid clone by dissociating the PML/RAR-alpha-RXR complex from the target genes and found to have a synergistic action with ATRA.[3].
==Gene Overview==
==Gene Overview==
The PML gene encodes a protein which functions via its association with nuclear bodies (NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. The protein acts as the scaffold for NBs allowing other proteins to shuttle in and out. Some of the Pml proteins diverse actions include: activating RB1; inhibiting AKT1; negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53.
The ''PML'' gene encodes a protein which functions via its association with nuclear bodies (NBs) in a wide range of important cellular processes including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. The protein acts as the scaffold for NBs, allowing other proteins to shuttle in and out. Some of the Pml proteins diverse actions include: activating ''RB1'', inhibiting ''AKT1'', negatively affecings the PI3K pathway by inhibiting MTOR and activating ''PTEN'', and positively regulates p53/''TP53''.
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. Unlike the normal retinoic acid receptor, the Pml-Rara protein does not respond to the ligand signal to induce transcription of genes, so the genes remain repressed, ultimately resulting in the inhibition of gene expression for hematopoietic differentiation and the maturation arrest of hematopoietic progenitors at the promyelocyte stage. In addition, while the normal PML protein blocks proliferation and induces apoptosis in combination with other proteins, the Pml-Rara protein acts as a dominant repressor of the normal PML protein [4].
Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML) that is almost entirely caused by the t(15;17)q22;q11) resulting in the PML-RARA fusion gene. Unlike the normal retinoic acid receptor, the Pml-Rara protein does not respond to the ligand signal to induce transcription of genes, so the genes remain repressed, ultimately resulting in the inhibition of gene expression for hematopoietic differentiation and the maturation arrest of hematopoietic progenitors at the promyelocyte stage. In addition, while the normal PML protein blocks proliferation and induces apoptosis in combination with other proteins, the Pml-Rara protein acts as a dominant repressor of the normal PML protein [4].
==Common Alteration Types==
==Common Alteration Types==
The translocation involving PML and RARA are found in more than 90% of cases of APL.
The translocation involving ''PML'' and ''RARA'' is found in more than 90% of APL cases.
{| 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
|-
|-
| || || || X || || X
| || || || || || X
|}
|}
==Internal Pages==
==Internal Pages==
[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/HAEM5:Acute_promyelocytic_leukaemia_with_PML::RARA_fusion 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/HAEM4:Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
[http://www.ccga.io/index.php/RARA RARA]
[http://www.ccga.io/index.php/RARA RARA]
==References==
==References==
1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.
1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p134-136.
2. Hsu, K.S. and Kao, H.Y. (2018). PML: Regulation and multifaceted function beyond tumor suppression. Cell. Bioscience 8: 5. PMID 29416846 PMCID: PMC5785837 DOI: 10.1186/s13578-018-0204-8.
2. Hsu, K.S. and Kao, H.Y. (2018). PML: Regulation and multifaceted function beyond tumor suppression. Cell. Bioscience 8: 5, PMID 29416846. DOI: 10.1186/s13578-018-0204-8.
3. Cingam, S. R. and Koshy, N.V. (2017). Cancer, Leukemia, Promyelocytic, Acute (APL, APML). https://www.ncbi.nlm.nih.gov/books/NBK459352/
3. Cingam, S. R. and Koshy, N.V. (2017). Cancer, Leukemia, Promyelocytic, Acute (APL, APML). https://www.ncbi.nlm.nih.gov/books/NBK459352/ Accessed August 3, 2018.
4. Schafer, E.S. . et al. (2015). Molecular Genetics of Acute Lymphoblastic Leukemia in The Molecular Basis of Cancer, 4th edition. Mendelsohn, J, Howley, PM, Israel, MA, Gray, JW, Thompson, CB. Editors. Elsevier Press: Philadelphia, USA, p395-406.
4. Schafer ES, et al., (2015). Molecular Genetics of Acute Lymphoblastic Leukemia in The Molecular Basis of Cancer, 4th edition. Mendelsohn, J, Howley, PM, Israel, MA, Gray, JW, Thompson, CB. Editors. Elsevier Press: Philadelphia, USA, p395-406.
5. Ng C.H. and Chng W.J. (2017). Recent advances in acute promyelocytic leukaemia. F1000Res. 6:1273. PMID 28794865 DOI: 10.12688/f1000research.10736.1
5. Ng CH and Chng WJ (2017). Recent advances in acute promyelocytic leukaemia. F1000Res 6:1273, PMID 28794865. DOI: 10.12688/f1000research.10736.1.
== Notes ==
== Notes ==