Acute promyelocytic leukemia pathophysiology: Difference between revisions
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* The ''PML-[[RARA gene|RARA]]'' [[Fusion gene|fusion]] [[Product (biology)|product]] is a [[Transcriptional regulation|transcriptional]] [[Regulator gene|regulator]] and [[Binding (molecular)|binds]] to [[retinoic acid]] response [[Chemical element|elements]] in the [[Promoter region|promoter regions]] of the [[genome]]. The PML-[[RARA gene|RARA]] [[Fusion gene|fusion]] [[Product (biology)|product]] serves to recruit co-repressors of [[gene]] [[Transcription (genetics)|transcription]], preventing [[myeloid]] [[differentiation]].<ref name="pmid26716387">{{cite journal| author=Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM| title=The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. | journal=Cancer | year= 2016 | volume= 122 | issue= 8 | pages= 1160-8 | pmid=26716387 | doi=10.1002/cncr.29852 | pmc=5042140 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26716387 }} </ref><ref name="urlRARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/gene/5914 |title=RARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI |format= |work= |accessdate=}}</ref> | * The ''PML-[[RARA gene|RARA]]'' [[Fusion gene|fusion]] [[Product (biology)|product]] is a [[Transcriptional regulation|transcriptional]] [[Regulator gene|regulator]] and [[Binding (molecular)|binds]] to [[retinoic acid]] response [[Chemical element|elements]] in the [[Promoter region|promoter regions]] of the [[genome]]. The PML-[[RARA gene|RARA]] [[Fusion gene|fusion]] [[Product (biology)|product]] serves to recruit co-repressors of [[gene]] [[Transcription (genetics)|transcription]], preventing [[myeloid]] [[differentiation]].<ref name="pmid26716387">{{cite journal| author=Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM| title=The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. | journal=Cancer | year= 2016 | volume= 122 | issue= 8 | pages= 1160-8 | pmid=26716387 | doi=10.1002/cncr.29852 | pmc=5042140 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26716387 }} </ref><ref name="urlRARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/gene/5914 |title=RARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI |format= |work= |accessdate=}}</ref> | ||
* This is known as a differentiation block, since the [[Cells (biology)|cells]] are unable to [[differentiate]] into normal mature [[cells]]. The [[Cells (biology)|cells]] remain primitive and stem-like, which is the basis for the [[malignancy]]. The result of the [[Chromosome|chromosomal]] [[Chromosomal translocation|translocation]] is ineffective [[blood]] [[Cell (biology)|cell]] production and uncontrolled proliferation of [[malignant]] promyelocytes.<ref name="pmid28529810">{{cite journal| author=Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A| title=Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia. | journal=Case Rep Hematol | year= 2017 | volume= 2017 | issue= | pages= 7657393 | pmid=28529810 | doi=10.1155/2017/7657393 | pmc=5424191 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28529810 }} </ref> | * This is known as a differentiation block, since the [[Cells (biology)|cells]] are unable to [[differentiate]] into normal mature [[cells]]. The [[Cells (biology)|cells]] remain primitive and stem-like, which is the basis for the [[malignancy]]. The result of the [[Chromosome|chromosomal]] [[Chromosomal translocation|translocation]] is ineffective [[blood]] [[Cell (biology)|cell]] production and uncontrolled proliferation of [[malignant]] promyelocytes.<ref name="pmid28529810">{{cite journal| author=Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A| title=Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia. | journal=Case Rep Hematol | year= 2017 | volume= 2017 | issue= | pages= 7657393 | pmid=28529810 | doi=10.1155/2017/7657393 | pmc=5424191 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28529810 }} </ref> | ||
* In 95% of cases of acute promyelocytic leukemia, the translocation involved ''PML'' and ''[[RARA gene|RARA]]''. However, it is important to note that ''[[RARA gene|RARA]]'' has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below. | * In 95% of cases of acute promyelocytic leukemia, the translocation involved ''PML'' and ''[[RARA gene|RARA]]''. However, it is important to note that ''[[RARA gene|RARA]]'' has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.1 | ||
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Revision as of 19:31, 10 January 2019
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Acute promyelocytic leukemia Microchapters |
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Differentiating Acute promyelocytic leukemia from other Diseases |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [3]
Overview
The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.
Pathophysiology
- The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.[1]
- The chromosomal translocation involves the juxtaposition of the retinoic acid receptor- alpha gene (RARA) on the long arm of chromosome 17 with another gene, most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15. The translocation is designated as t(15;17)(q22;q12).[2][3]
- The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome. The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.[4][5]
- This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The cells remain primitive and stem-like, which is the basis for the malignancy. The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.[2]
- In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.1
| Translocation Partner | Chromosomal Location | Function | Response to Therapy | Other Features |
|---|---|---|---|---|
|
PML |
15q24.1 |
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|
|
|
11q23.2 |
|
|
| |
|
NPM1 |
5q35.1 |
|
|
|
|
NUMA[6] |
11q13.4 |
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|
|
|
STAT5B[7] |
17q21.2 |
|
|
|
References
- ↑ Zelent, Arthur; Guidez, Fabien; Melnick, Ari; Waxman, Samuel; Licht, Jonathan D (2001). "Translocations of the RARα gene in acute promyelocytic leukemia". Oncogene. 20 (49): 7186–7203. doi:10.1038/sj.onc.1204766. ISSN 0950-9232.
- ↑ 2.0 2.1 2.2 Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A (2017). "Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia". Case Rep Hematol. 2017: 7657393. doi:10.1155/2017/7657393. PMC 5424191. PMID 28529810.
- ↑ L. R. Hiorns, T. Min, G. J. Swansbury, A. Zelent, M. J. Dyer & D. Catovsky (1994). "Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17". Blood. 83 (10): 2946–2951. PMID 8180390. Unknown parameter
|month=ignored (help) - ↑ Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). "The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy". Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.
- ↑ "RARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI".
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). "Emerging new approaches for the treatment of acute promyelocytic leukemia". Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.
- ↑ 7.0 7.1 7.2 Chen C, Huang X, Wang K, Chen K, Gao D, Qian S (2018). "Early mortality in acute promyelocytic leukemia: Potential predictors". Oncol Lett. 15 (4): 4061–4069. doi:10.3892/ol.2018.7854. PMC 5835847. PMID 29541170.