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==Pathophysiology==
==Pathophysiology==
The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in [[hematopoietic stem cells]]. 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.<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> The translocation is designated as t(15;17)(q22;q12). The ''PML-RARA'' fusion product is a transcriptional regulator and prevents myeloid differentiation. This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The result of the chromosomal translocation is ineffective blood 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''. However, it is important to note that ''RARA'' has multiple other binding partners which can lead to the development or acute promyelocytic leukemia.  
The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in [[hematopoietic stem cells]]. 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.<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> The translocation is designated as t(15;17)(q22;q12). The ''PML-RARA'' fusion product is a transcriptional regulator and prevents myeloid differentiation. This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The result of the chromosomal translocation is ineffective blood 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''. 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.


Four other gene rearrangements have been described in APL fusing ''RARα'' to promyelocytic leukemia zinc finger (''PLZF'' or ''ZBTB16''), nucleophosmin (''NPM''), nuclear matrix associated (''NUMA''), or signal transducer and activator of transcription  5b (''STAT5B'') genes., ZBTB16


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==References==
==References==

Revision as of 21:55, 10 May 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Pathophysiology

The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells. 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.[1] The translocation is designated as t(15;17)(q22;q12). The PML-RARA fusion product is a transcriptional regulator and prevents myeloid differentiation. This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.[1] 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.


Translocation Partner Chromosomal Location Function Other Features

PML

15q24.1

  • A member of the tripartite motif (TRIM) family
  • Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor
  • Regulate p53 response to oncogenic growth signals
  • Influenced by the cell cycle
  • Most common translocation

PLZF (ZBTB16)

11q23.2

  • Encodes a zinc finger transcription factor
  • Involved in cell cycle regulation
  • Interacts with histone deacetylases
  • Second most common translocation (after PML-RARA)

NPM1

5q35.1

  • Encodes nucleophosmin 1 (a nucleolar shuttle protein)
  • Involved in centromere duplication
  • Serves a protein chaperone
  • Regulates the cell cycle
  • Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation

NUMA

11q13.4

  • Contributes to a structural component of the nuclear matrix
  • Interacts with microtubules
  • Contributes to mitotic spindle formation during cell division
  • Rare translocation

STAT5B

17q21.2

  • Encodes a signal transducer and activator of transcription (STAT)
  • Serves an intracellular transduction molecule for cytokine signaling
  • Translocates to the nucleus and functions as a transcription factor
  • Involved in T cell receptor signaling
  • Involved in apoptosis
  • Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation
  • Rare translocation

References

  1. ↑ 1.0 1.1 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.

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