Difference between revisions of "PML"

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==Cancer Category/Type==
 
==Cancer Category/Type==
  
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Acute Promyelocytic Leukemia (APL)
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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].
  
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Acute promyelocytic leukemia is a relatively rare and comprises about 7% to 8% of adult AML cases. Acute promyelocytic leukemia is usually seen in middle-aged people with a median age of 47 years. Acute promyelocytic leukemia occurs very rarely before the age of 20. [3].
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[http://www.ccga.io/index.php/Acute_Promyelocytic_Leukemia_(APL)_with_PML-RARA Acute Promyelocytic Leukemia (APL) with PML-RARA]
  
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(90% to 95%) of the cases, APL results from a t (15;17) (q22;q21) translocation resulting in the head to tail fusion of the promyelocytic leukemia (PML) gene, to RAR-alpha to generate two fusion genes, PML-RARalpha and a reciprocal RAR-alpha-PML (80%) that encode a protein, which functions as an aberrant retinoid receptor [3].
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[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
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Responsive to retinoid treatment
 
  
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The PML/RARa protein heterodimerizes with the retinoid X receptor (RXR), the resulting PML/RARa-RXR complex binds to retinoic acid-responsive elements in target genes, resulting in cessation of myeloid differentiation at the promyelocytic stage. The excessive promyelocytes [3].
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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]
 
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]
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==Gene Overview==
 
==Gene Overview==
  
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localizes to nuclear bodies where it functions as a transcription factor and tumor suppressor. Its expression is cell-cycle related and it regulates the p53 response to oncogenic signals. The gene is often involved in the translocation with the retinoic acid receptor alpha gene associated with acute promyelocytic leukemia (APL).
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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.  
  
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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 [2].
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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==
 
==Common Alteration Types==
  
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Put your text here and/or fill in the table with an X where applicable
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The translocation involving PML and RARA are found in more than 90% of cases of APL.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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! 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  
 
|-
 
|-
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| EXAMPLE: X ||EXAMPLE: X || EXAMPLE: X  || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X
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| ||  ||   || X || || X
 
|}
 
|}
  
 
==Internal Pages==
 
==Internal Pages==
  
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Put your text here
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[http://www.ccga.io/index.php/Acute_Promyelocytic_Leukemia_(APL)_with_PML-RARA Acute Promyelocytic Leukemia (APL) with PML-RARA]
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EXAMPLE [[Germline Cancer Predisposition Genes]]
 
  
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==External Links==
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[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_and_Related_Precursor_Neoplasms Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]
  
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Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.
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[http://www.ccga.io/index.php/RARA RARA]
  
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EXAMPLES
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==External Links==
  
 
'''[http://atlasgeneticsoncology.org/Genes/GC_PML.html ''PML'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
 
'''[http://atlasgeneticsoncology.org/Genes/GC_PML.html ''PML'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
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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/
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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.
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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 ==
 
== Notes ==

Revision as of 16:58, 1 August 2018

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

RARA

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

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

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