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→Genetics: Updated genetics section. t(2;8) and t(8;22) translocations are 15 and 5% of cases of Burkitt respectively. Source from a textbook from 2009 was updated by using a review article from NEJM 9/2022. Regarding DDX3X and DDX3Y, please see graphical abstract in the article. |
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==Pathophysiology==
===Genetics===
All types of Burkitt lymphoma are characterized by dysregulation of the ''[[c-myc]]'' gene by one of three [[chromosomal translocation]]s which place the myc gene under the control of an immunoglobulin gene enhancer.<ref name=Hoffman>{{cite book|last=Hoffman|first=Ronald|title=Hematology : basic principles and practice|year=2009|publisher=Churchill Livingstone/Elsevier|location=Philadelphia, PA|isbn=978-0-443-06715-0|pages=1304–1305|url=http://www.mdconsult.com/das/book/pdf/331595517-4/978-0-443-06715-0/4-u1.0-B978-0-443-06715-0..50083-2..DOCPDF.pdf?isbn=978-0-443-06715-0&eid=4-u1.0-B978-0-443-06715-0..50083-2..DOCPDF|edition=5th}}</ref>
* The most common variant is t(8;14)(q24;q32), which accounts for about
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The c-myc gene found on chromosome 8 is part of the Myc family of genes that serve as regulators of cellular transcription and is associated with Burkitt lymphoma.<ref name=":3">{{Cite book|url=https://www.worldcat.org/oclc/1191840836|title=Robbins & Cotran pathologic basis of disease|date=2021|others=Vinay Kumar, Abul K. Abbas, Jon C. Aster|isbn=978-0-323-53113-9|edition=10th|location=Philadelphia, PA|pages=583–633|oclc=1191840836}}</ref><ref name=":0" /> Expression of the c-myc gene results in the synthesis of [[Transcription factor|transcriptional factors]] that increase the expression of other genes involved in [[aerobic glycolysis]].<ref name=":3" /> Ultimately, an increase in aerobic glycolysis plays a role in providing the necessary energy for cellular growth to occur.<ref name=":3" /> The translocation of the c-myc gene to the IGH, IGK, or IGL region moves the gene to a location in the genome near immunoglobulin enhancers which increases the expression of the c-myc gene.<ref name=":3" /> Overall, this translocation leads to increased cellular proliferation that is found in Burkitt lymphoma.<ref name=":3" /> Point mutations can also be present in the translocated c-myc gene resulting in the expressed c-myc protein being overactive.<ref name=":3" />
Bcl-2 translocations, which are frequently seen in [[follicular lymphoma|follicular lymphomas]] and other B-cell Non-Hodgkin Lymphomas, do not occur in Burkitt lymphomas.
▲The c-myc gene found on chromosome 8 is part of the Myc family of genes that serve as regulators of cellular transcription and is associated with Burkitt lymphoma.<ref name=":3">{{Cite book|url=https://www.worldcat.org/oclc/1191840836|title=Robbins & Cotran pathologic basis of disease|date=2021|others=Vinay Kumar, Abul K. Abbas, Jon C. Aster|isbn=978-0-323-53113-9|edition=10th|location=Philadelphia, PA|pages=583–633|oclc=1191840836}}</ref><ref name=":0" /> Expression of the c-myc gene results in the synthesis of [[Transcription factor|transcriptional factors]] that increase the expression of other genes involved in [[aerobic glycolysis]].<ref name=":3" /> Ultimately, an increase in aerobic glycolysis plays a role in providing the necessary energy for cellular growth to occur.<ref name=":3" /> The translocation of the c-myc gene to the IGH, IGK, or IGL region moves the gene to a location in the genome near immunoglobulin enhancers which increases the expression of the c-myc gene.<ref name=":3" /> Overall, this translocation leads to increased cellular proliferation that is found in Burkitt lymphoma.<ref name=":3" /> Point mutations can also be present in the translocated c-myc gene resulting in the expressed c-myc protein being overactive.<ref name=":3" /> Other mutations found include the TCF transcription factor mutation, which increases cellular proliferation via the increased expression of other genes.<ref name=":3" /> Along with mutations that support cell proliferation, Burkitt lymphoma has been found to also harbor mutations in the TP53 gene that is a [[Tumor suppressor gene|tumor suppressor]] and would normally function to limit cellular growth.<ref name=":0" />
One of the above described translocations of Myc is seen in 90% of cases of Burkitt lymphoma, but these oncogenic translocations are not usually sufficient to cause lymphoma; other mutations must also be present. These additional mutations include mutations of the tumor suppressor [[TP53]], which interacts with the tumor suppressor [[p53]] (which usually causes apoptosis in B cells carrying the disordered MYC oncoprotein). But with TP53 and p53 mutated, apoptosis is blocked, and the oncogenic B-cells are allowed to proliferate unchecked. The tumor suppressors [[p14arf|ARF]] and [[USP7]] are also frequently mutated in Burkitt lymphoma leading to [[MDM2]] inhibition of the tumor suppressor p53 which then leads to enhanced oncogenesis. [[SIN3A]], a regulator of MYC, that acts to inhibit MYC by [[acetylation|deacetylating]] it, is often inactivated in Burkitt lymphoma. Also, sequential mutations of the RNA helicases (involved in RNA synthesis) [[DDX3X]] (found on the [[x chromosome]] and [[DDX3Y]] (found on the [[y chromosome]]) lead to MYC oncogenesis in Burkitt lymphoma.<ref name="Gong 2021">{{cite journal |last1=Gong |first1=Chun |last2=Krupka |first2=Joanna A. |last3=Gao |first3=Jie |last4=Grigoropoulos |first4=Nicholas F. |last5=Giotopoulos |first5=George |last6=Asby |first6=Ryan |last7=Screen |first7=Michael |last8=Usheva |first8=Zelvera |last9=Cucco |first9=Francesco |last10=Barrans |first10=Sharon |last11=Painter |first11=Daniel |last12=Zaini |first12=Nurmahirah Binte Mohammed |last13=Haupl |first13=Björn |last14=Bornelöv |first14=Susanne |last15=Ruiz De Los Mozos |first15=Igor |last16=Meng |first16=Wei |last17=Zhou |first17=Peixun |last18=Blain |first18=Alex E. |last19=Forde |first19=Sorcha |last20=Matthews |first20=Jamie |last21=Khim Tan |first21=Michelle Guet |last22=Burke |first22=G.A. Amos |last23=Sze |first23=Siu Kwan |last24=Beer |first24=Philip |last25=Burton |first25=Cathy |last26=Campbell |first26=Peter |last27=Rand |first27=Vikki |last28=Turner |first28=Suzanne D. |last29=Ule |first29=Jernej |last30=Roman |first30=Eve |last31=Tooze |first31=Reuben |last32=Oellerich |first32=Thomas |last33=Huntly |first33=Brian J. |last34=Turner |first34=Martin |last35=Du |first35=Ming-Qing |last36=Samarajiwa |first36=Shamith A. |last37=Hodson |first37=Daniel J. |title=Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis |journal=Molecular Cell |date=October 2021 |volume=81 |issue=19 |pages=4059–4075.e11 |doi=10.1016/j.molcel.2021.07.041}}</ref> Early in the pathogenesis process, DDX3X mutations limit translation (protein synthesis) allowing lymphoma cells to escape MYC induced proteotoxic stress and apoptosis, then later, DDX3Y mutations restore high level protein synthesis (by producing the [[translation (biology)|translational]] machinery) and leading to increased proliferation of tumor cells. These sequential DDX3X and DDX3Y mutations are thought to partially explain why Burkitt lymphoma is more common in males as the DDX3Y RNA helicase is only found on the Y chromosome. Mutations affecting the transcription factor [[TCF3]] and its negative regulator [[ID3 (gene)|ID3]] are found in about 70% of cases of Burkitt lymphoma. These mutations prevent ID3 from binding to and inhibiting TCF3; thus the hyperactive TCF3 then activates [[B cell receptor|B cell receptors]] which activate [[PI3K]] and [[mTOR]], as well as Ig heavy and light chain genes, which contribute to oncogenesis.<ref name=":3" /> TCF3 and ID3 mutations lead to continuously active B-cell receptors, explaining the high level of proliferation seen in Burkitt lymphoma. The cell cycle regulators [[Cyclin D3]] and [[p16]] may also be activated and deactivated respectively in Burkitt lymphoma; leading to massive tumor cell proliferation.
Some epigenetic mechanisms have been found to play a role in the pathogenesis of Burkitt lymphoma. [[FBXO11]] is a chromatin regulator. By activating [[ubiquitin ligase]], FBXO11 causes ubiquitination of [[BCL6]] which causes it to be targeted for proteasome degradation. BCL6 normally helps B cells mature in the germinal center and produce antibodies specific to encountered antigens. In Burkitt lymphoma, FBXO11 is deactivated, leading to increased BCL6 activation which then leads to increased proliferation and decreased maturation of germinal center B-cells, thus promoting lymphomagenesis.
EBV associated Burkitts has increased expressional activity of [[activation-induced cytidine deaminase]], which is a mutator, this leads to EBV associated Burkitt lymphomas having more mutations than non-EBV types. Non-EBV subtypes of Burkitt lymphoma more commonly have dysregulation of cyclin D3 and mutated, inactivated p53.
=== Virology ===
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