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==Pathophysiology==
==Pathophysiology==
 
The pathophysiology of myeloproliferative neoplasms is based on the specific subtype of myeloproliferative neoplasm. Primary cytogenetic abnormalities have not been identified in the majority of myeloproliferative neoplasms. Aberrant activation of [[tyrosine kinase]]s and associated signaling pathways is frequently implicated as the disease-initiating event.
==Genetics==
Primary cytogenetic abnormalities have not been identified in the majority of myeloproliferative neoplasms. Aberrant activation of [[tyrosine kinase]]s and associated signaling pathways is frequently implicated as the disease-initiating event.
 
===Chronic Myelogenous Leukemia===
In [[Philadelphia chromosome]] translocation, parts of two chromosomes (the 9<sup>th</sup> and 22<sup>nd</sup> by conventional [[karyotype|karyotypic]] numbering) switch places. As a result, part of the ''BCR'' ("breakpoint cluster region") gene from chromosome 22 is fused with the ''ABL'' gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a [[tyrosine kinase]]), the ''[[BCR]]-[[ABL]]''  fusion gene product is also a tyrosine kinase.
The fused ''[[BCR]]-[[ABL]]''  protein interacts with the interleukin 3beta c receptor subunit. The ''[[BCR]]-[[ABL]]'' transcript is continuously active and does not require activation by other cellular messaging proteins. In turn ''[[BCR]]-[[ABL]]''  activates a cascade of proteins which control the [[cell cycle]], speeding up cell division. Moreover the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the ''[[BCR]]-[[ABL]]''  protein is the pathophysiologic cause of chronic myelogenous leukemia.<ref name="Hehlmann">{{cite journal|title=Chronic myeloid leukaemia|author=Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet|journal=Lancet|volume=370|issue=9584|pages=342-50|date=2007|pmid=17662883}}</ref>


===Polycythemia Vera===
===Polycythemia Vera===
Line 24: Line 18:
===Essential Thrombocythemia===
===Essential Thrombocythemia===
[[Calreticulin]] gene (''CALR'') gene involved in the pathogenesis of essential thrombocythemia.<ref name="pmidhttp://dx.doi.org/10.1182/blood-2013-11-538983">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1182/blood-2013-11-538983 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
[[Calreticulin]] gene (''CALR'') gene involved in the pathogenesis of essential thrombocythemia.<ref name="pmidhttp://dx.doi.org/10.1182/blood-2013-11-538983">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1182/blood-2013-11-538983 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
===Chronic Myelogenous Leukemia===
In [[Philadelphia chromosome]] translocation, parts of two chromosomes (the 9<sup>th</sup> and 22<sup>nd</sup> by conventional [[karyotype|karyotypic]] numbering) switch places. As a result, part of the ''BCR'' ("breakpoint cluster region") gene from chromosome 22 is fused with the ''ABL'' gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a [[tyrosine kinase]]), the ''[[BCR]]-[[ABL]]''  fusion gene product is also a tyrosine kinase.
The fused ''[[BCR]]-[[ABL]]''  protein interacts with the interleukin 3beta c receptor subunit. The ''[[BCR]]-[[ABL]]'' transcript is continuously active and does not require activation by other cellular messaging proteins. In turn ''[[BCR]]-[[ABL]]''  activates a cascade of proteins which control the [[cell cycle]], speeding up cell division. Moreover the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the ''[[BCR]]-[[ABL]]''  protein is the pathophysiologic cause of chronic myelogenous leukemia.<ref name="Hehlmann">{{cite journal|title=Chronic myeloid leukaemia|author=Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet|journal=Lancet|volume=370|issue=9584|pages=342-50|date=2007|pmid=17662883}}</ref>
===Primary Myelofibrosis===
===Primary Myelofibrosis===
Genes involved in the pathogenesis of primary myelofibrosis include [[Janus kinase 2]] ([[JAK2]] kinase) and  [[Calreticulin]] (''CALR'').<ref name="ganfyd">Ganfyd. Myelofibrosis2015.http://www.ganfyd.org/index.php?title=Primary_myelofibrosis</ref> Primary myelofibrosis is hallmarked by clonal myeloproliferation with reactive stromal changes in response to uncontrolled production of growth factors (e.g., [[TGF beta|transforming growth factor β]], [[platelet-derived growth factor|platelet-derived growth factor]], and [[basic fibroblast growth factor|basic fibroblast growth factor]]) from resident [[megakaryocytes]] and [[monocytes]]. The etiopathogenic mutations leading to primary myelofibrosis remain unclear.<ref>{{cite book | last = Jaffe | first = Elaine | title = Pathology and genetics of tumours of haematopoietic and lymphoid tissues | publisher = IARC Press Oxford University Press | year = 2001 | isbn = 978-9283224112 }}</ref>
Genes involved in the pathogenesis of primary myelofibrosis include [[Janus kinase 2]] ([[JAK2]] kinase) and  [[Calreticulin]] (''CALR'').<ref name="ganfyd">Ganfyd. Myelofibrosis2015.http://www.ganfyd.org/index.php?title=Primary_myelofibrosis</ref> Primary myelofibrosis is hallmarked by clonal myeloproliferation with reactive stromal changes in response to uncontrolled production of growth factors (e.g., [[TGF beta|transforming growth factor β]], [[platelet-derived growth factor|platelet-derived growth factor]], and [[basic fibroblast growth factor|basic fibroblast growth factor]]) from resident [[megakaryocytes]] and [[monocytes]]. The etiopathogenic mutations leading to primary myelofibrosis remain unclear.<ref>{{cite book | last = Jaffe | first = Elaine | title = Pathology and genetics of tumours of haematopoietic and lymphoid tissues | publisher = IARC Press Oxford University Press | year = 2001 | isbn = 978-9283224112 }}</ref>

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Overview

Clinical and pathologic features in the myeloproliferative neoplasms are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in altered populations of granulocytes, erythrocytes, or platelets in the peripheral blood.

Pathophysiology

The pathophysiology of myeloproliferative neoplasms is based on the specific subtype of myeloproliferative neoplasm. Primary cytogenetic abnormalities have not been identified in the majority of myeloproliferative neoplasms. Aberrant activation of tyrosine kinases and associated signaling pathways is frequently implicated as the disease-initiating event.

Polycythemia Vera

  • Gene involved in the pathogenesis of polycythemia vera is Janus kinase 2 (JAK2 kinase) will lead to activation of the following pathways:[1]
  • JAK-STAT
  • PI3K (phosphoinositide-3-kinase)
  • AKT (protein kinase B)
  • The activation of these pathways causes neoplastic proliferation and maturation of erythroid cells.

Essential Thrombocythemia

Calreticulin gene (CALR) gene involved in the pathogenesis of essential thrombocythemia.[2]

Chronic Myelogenous Leukemia

In Philadelphia chromosome translocation, parts of two chromosomes (the 9th and 22nd by conventional karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR-ABL fusion gene product is also a tyrosine kinase. The fused BCR-ABL protein interacts with the interleukin 3beta c receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn BCR-ABL activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.[3]

Primary Myelofibrosis

Genes involved in the pathogenesis of primary myelofibrosis include Janus kinase 2 (JAK2 kinase) and Calreticulin (CALR).[1] Primary myelofibrosis is hallmarked by clonal myeloproliferation with reactive stromal changes in response to uncontrolled production of growth factors (e.g., transforming growth factor β, platelet-derived growth factor, and basic fibroblast growth factor) from resident megakaryocytes and monocytes. The etiopathogenic mutations leading to primary myelofibrosis remain unclear.[4]

Gallery

  • Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.[5]

    Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.[5]

  • Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell[5]

    Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell[5]

References

  1. ↑ 1.0 1.1 Ganfyd. Polycythaemia vera 2015.http://www.ganfyd.org/index.php?title=Polycythemia_vera
  2. ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1182/blood-2013-11-538983 Check |pmid= value (help).
  3. ↑ Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). "Chronic myeloid leukaemia". Lancet. 370 (9584): 342–50. PMID 17662883.
  4. ↑ Jaffe, Elaine (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press Oxford University Press. ISBN 978-9283224112.
  5. ↑ 5.0 5.1 National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq
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