Editing Essential thrombocythemia (section)

==Cause==
In ET, [[megakaryocyte]]s are more sensitive to [[growth factors]].<ref>{{cite journal|doi=10.1111/j.1600-0609.1975.tb01087.x|vauthors=Branehog I, Ridell B, Swolin B, Weinfeld A | year=1975 |title=Megakaryocyte quantifications in relation to thrombokinetics in primary thrombocythaemia and allied diseases |journal=Scand. J. Haematol.| volume=15 | pages=321–32|pmid=1060175|issue=5}}</ref> Platelets derived from the abnormal megakaryocytes are activated, which, along with the elevated platelet count, contributes to the likelihood of forming blood clots.<ref name="path2">{{cite journal |last=Vannucchi |first=AM |s2cid=510829 |title=Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia |journal=Internal and Emergency Medicine |date=June 2010 |volume=5 |issue=3 |pages=177–84 |doi=10.1007/s11739-009-0319-3 |pmid=19789961}}</ref> The increased possibility of bleeding when the platelet count is over 1 million is due to [[von Willebrand factor]] (vWF) sequestration by the increased mass of platelets, leaving insufficient vWF for [[platelet]] adhesion.<ref name="path2" /> A mutation in the [[JAK2]] [[kinase]] (V617F) is present in 40–50% of cases and is diagnostic if present.<ref name="path" /><ref name="path2" /> ''JAK2'' is a member of the [[Janus kinase]] family.<ref name="path" /><ref name="path2" />

In 2013, two groups detected [[calreticulin]] mutations in a majority of [[Janus kinase 2|JAK2]]-negative/[[thrombopoietin receptor|MPL]]-negative patients with essential thrombocythemia and [[myelofibrosis|primary myelofibrosis]], which makes ''CALR'' mutations the second most common in [[myeloproliferative disease|myeloproliferative neoplasms]]. All mutations (insertions or deletions) affected the last exon, generating a reading [[Frameshift mutation|frame shift]] of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum [[ER retention|KDEL retention signal]].<ref name="pmid24325359">{{cite journal |vauthors=Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR |title=Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2 |journal=The New England Journal of Medicine |volume=369 |issue=25 |pages=2391–405 |date=Dec 2013 |pmid=24325359 |pmc=3966280 |doi=10.1056/NEJMoa1312542}}</ref><ref name="pmid24325356">{{cite journal |vauthors=Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R |s2cid=14787432 |title=Somatic mutations of calreticulin in myeloproliferative neoplasms |journal=The New England Journal of Medicine |volume=369 |issue=25 |pages=2379–90 |date=Dec 2013 |pmid=24325356 |doi=10.1056/NEJMoa1311347|doi-access=free }}</ref>

There are three known genetic mutations that cause ET. The most common genetic mutation is a JAK2 mutation. Roughly 50% of the population of ET patients have this mutation. The JAK 2 gene signals a protein that promotes the growth of cells. The protein is part of a signaling pathway called the JAK/STAT pathway. The JAK2 protein controls the production of blood cells from hematopoietic stem cells which are located in the bone marrow and can eventually become platelets, red blood cells or white blood cells. Specifically in ET, a JAK2 mutation is acquired rather than inherited. The most common JAK2 mutation is V617F which is the replacement of a valine amino acid with phenylalanine amino acid at the 617 position, hence the name V617F. This mutation results in the JAK2 protein constantly being turned on, which leads to the overproduction of abnormal blood cells, in ET it is platelets or megakaryocytes. There is also another JAK2 mutation found in exon 12, however much less common.

There is also a small number of people who have a different mutation called CALR, which is abbreviated from calreticulin. CALR is a protein found in the endoplasmic reticulum (ER). Its purpose is to maintain calcium homeostasis and control protein folding. There are three parts to CALR including an amino acid domain, a proline rich P-domain, and a carboxyl domain. All of these parts facilitate the function of CALR. CALR mutation is caused by insertions or deletions of amino acids in exon 9 that cause a reading shift, which then leads to the formation of a novel C terminus. There are two common types of CALR mutations, type 1 and type 2. Type 1 mutations are a 52-bp deletion and type 2 mutations are a 5-bp insertion. In type 1 mutations, the negatively charged amino acids in the CALR C terminus are completely eliminated, and in the type 2 mutations, roughly half are eliminated. There are other mutations involving CALR, however these two are the most common.<ref>{{Cite journal |last1=Prins |first1=Daniel |last2=González Arias |first2=Carlos |last3=Klampfl |first3=Thorsten |last4=Grinfeld |first4=Jacob |last5=Green |first5=Anthony R. |date=February 2020 |title=Mutant Calreticulin in the Myeloproliferative Neoplasms |journal=HemaSphere |language=en |volume=4 |issue=1 |pages=e333 |doi=10.1097/HS9.0000000000000333 |issn=2572-9241 |pmc=7000472 |pmid=32382708}}</ref>

Lastly, the least common mutation found in patients with ET are MPL mutations. The MPL gene is responsible for making thrombopoeitin receptor proteins which promote the growth and division of cells. This receptor protein is vital in producing platelets. There are various MPL mutations, but most typical are point mutations that cause amino acid changes. The MPL mutation activates the thrombopoeitin receptor despite the absence of the ligand. This causes the constant proliferation of cells.<ref>{{Citation |last1=Guglielmelli |first1=Paola |title=The MPL mutation |date=2021 |journal=International Review of Cell and Molecular Biology |volume=365 |pages=163–178 |url=https://linkinghub.elsevier.com/retrieve/pii/S1937644821001076 |access-date=2024-05-07 |publisher=Elsevier |language=en |doi=10.1016/bs.ircmb.2021.09.003 |isbn=978-0-323-89939-0 |last2=Calabresi |first2=Laura|pmid=34756243 |url-access=subscription }}</ref>