PML
Primary Author(s)*
Brian Davis PhD
Synonyms
"Promyelocytic Leukemia"; "Tripartite Motif-Containing Protein 19"; TRIM19; "RING Finger Protein 71"; RNF71; MYL
Genomic Location
Cytoband: 15q24.1
Genomic Coordinates:
chr15:74,287,014-74,340,160(GRCh37/hg19)
chr15:73,994,673-74,047,819(GRCh38/hg38)
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].
Acute Promyelocytic Leukemia (APL) with PML-RARA
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 all-trans retinoic acid (ATRA) or arsenic trioxide [1, 2, 3, 4].
Acute promyelocytic leukemia is a medical emergency with a very high pre-treatment mortality. All-Trans Retinoic Acid (ATRA) is the mainstay in the treatment of acute promyelocytic leukemia and used in all modern regimens. [3]
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
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.
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].
Common Alteration Types
The translocation involving PML and RARA are found in more than 90% of cases of APL.
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| X | X |
Internal Pages
Acute Promyelocytic Leukemia (APL) with PML-RARA
Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms
External Links
PML by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
PML by COSMIC - sequence information, expression, catalogue of mutations
PML-RARA by CIViC - general knowledge and evidence-based variant specific information
PML by St. Jude ProteinPaint mutational landscape and matched expression data.
PML by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
PML by Cancer Index - gene, pathway, publication information matched to cancer type
PML by My Cancer Genome - brief gene overview
PML by UniProt - protein and molecular structure and function
PML by Pfam - gene and protein structure and function information
PML by GeneCards - general gene information and summaries
"PML" by NCBI Gene - general gene information and summaries
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.
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.
3. Cingam, S. R. and Koshy, N.V. (2017). Cancer, Leukemia, Promyelocytic, Acute (APL, APML). https://www.ncbi.nlm.nih.gov/books/NBK459352/
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.
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
Notes
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