Compendium of Cancer Genome Aberrations

HAEM5:Adult T-cell leukaemia/lymphoma: Difference between revisions

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{| class="wikitable"
{| class="wikitable"
|+
|Acceptable
|Acceptable
|Adult T-cell leukaemia/lymphoma, HTLV-1 associated
|Adult T-cell leukaemia/lymphoma, HTLV-1 associated
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==Gene Rearrangements==
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
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|Deletions, inversions, duplications, translocations at '''9p24.1''' disrupting 3′-UTR
|Deletions, inversions, duplications, translocations at '''9p24.1''' disrupting 3′-UTR
|Common (≈20–25% of ATLL in large cohorts)
|Common (≈20–25% of ATLL in large cohorts)
|
|T
|No
|No
|Highlights immune-evasion axis and immune checkpoint biology, but PD-1 blockade has shown harm and induced rapid progression in ATLL<ref>{{Cite journal|last=Rauch|first=Daniel A.|last2=Conlon|first2=Kevin C.|last3=Janakiram|first3=Murali|last4=Brammer|first4=Jonathan E.|last5=Harding|first5=John C.|last6=Ye|first6=B. Hilda|last7=Zang|first7=Xingxing|last8=Ren|first8=Xiaoxin|last9=Olson|first9=Sydney|date=2019-10-24|title=Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade|url=https://pubmed.ncbi.nlm.nih.gov/31467059|journal=Blood|volume=134|issue=17|pages=1406–1414|doi=10.1182/blood.2019002038|issn=1528-0020|pmc=6839957|pmid=31467059}}</ref>
|Highlights immune-evasion axis and immune checkpoint biology, but PD-1 blockade has shown harm and induced rapid progression in ATLL<ref>{{Cite journal|last=Rauch|first=Daniel A.|last2=Conlon|first2=Kevin C.|last3=Janakiram|first3=Murali|last4=Brammer|first4=Jonathan E.|last5=Harding|first5=John C.|last6=Ye|first6=B. Hilda|last7=Zang|first7=Xingxing|last8=Ren|first8=Xiaoxin|last9=Olson|first9=Sydney|date=2019-10-24|title=Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade|url=https://pubmed.ncbi.nlm.nih.gov/31467059|journal=Blood|volume=134|issue=17|pages=1406–1414|doi=10.1182/blood.2019002038|issn=1528-0020|pmc=6839957|pmid=31467059}}</ref>
|}
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
Tandem duplications of  2q33.2 segments cause formation of CTLA4-CD28 and ICOS-CD28 fusion products that render prolonged co-stimulatory signals<ref name=":1">{{Cite journal|last=Kataoka|first=Keisuke|last2=Nagata|first2=Yasunobu|last3=Kitanaka|first3=Akira|last4=Shiraishi|first4=Yuichi|last5=Shimamura|first5=Teppei|last6=Yasunaga|first6=Jun-Ichirou|last7=Totoki|first7=Yasushi|last8=Chiba|first8=Kenichi|last9=Sato-Otsubo|first9=Aiko|date=2015-11|title=Integrated molecular analysis of adult T cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26437031|journal=Nature Genetics|volume=47|issue=11|pages=1304–1315|doi=10.1038/ng.3415|issn=1546-1718|pmid=26437031}}</ref>.
{| class="wikitable sortable"
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|''REL (c-Rel)''
|3′ truncations (no partner gene; gain-of-function)<ref>{{Cite journal|last=Kogure|first=Yasunori|last2=Kameda|first2=Takuro|last3=Koya|first3=Junji|last4=Yoshimitsu|first4=Makoto|last5=Nosaka|first5=Kisato|last6=Yasunaga|first6=Jun-ichirou|last7=Imaizumi|first7=Yoshitaka|last8=Watanabe|first8=Mizuki|last9=Saito|first9=Yuki|date=2022-02-17|title=Whole-genome landscape of adult T-cell leukemia/lymphoma|url=https://ashpublications.org/blood/article/139/7/967/477456/Whole-genome-landscape-of-adult-T-cell-leukemia|journal=Blood|language=en|volume=139|issue=7|pages=967–982|doi=10.1182/blood.2021013568|issn=0006-4971|pmc=8854674|pmid=34695199}}</ref>
|C-terminal truncation removes negative-regulatory regions → transcription upregulation/activation of REL → NF-κB pathway activation
|'''2p16.1''' 3′-end truncating rearrangements
|Recurrent (~13%)
|
|No
|
|-
|-
|2q33.2 (Tandem Duplication)
|''CD28''
|5’ CTLA/3’CD28
|''CTLA4::CD28''
|der(2)
''ICOS::CD28''
|7%
|In-frame fusion converts inhibitory CTLA4/ICOS extracellular domains into CD28 signaling tail → constitutive co-stimulation
|Rearrangements within '''2q33''' region (CTLA4/ICOS/CD28 are clustered); interstitial events/inversions
|Rare, but enriched in younger patients (3/8 cases, 37.5%<ref>{{Cite journal|last=Yoshida|first=Noriaki|last2=Shigemori|first2=Kay|last3=Donaldson|first3=Nicholas|last4=Trevisani|first4=Christopher|last5=Cordero|first5=Nicolas A.|last6=Stevenson|first6=Kristen E.|last7=Bu|first7=Xia|last8=Arakawa|first8=Fumiko|last9=Takeuchi|first9=Mai|date=2020-04-23|title=Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions|url=https://pubmed.ncbi.nlm.nih.gov/31961925|journal=Blood|volume=135|issue=17|pages=1467–1471|doi=10.1182/blood.2019001815|issn=1528-0020|pmc=7180081|pmid=31961925}}</ref>)
|T
|No
|Potential for CTLA4 blockade as treatment when CD28 fusions are present
|-
|-
|2q33.2 (Tandem Duplication)
|''BCL11B''
|5’ICOS/3’CD28
|''HELIOS (IKZF2)::BCL11B''
|der(2)
|Transcription-factor fusion likely deregulates T-cell developmental programs
|7%
|'''t(2;14)(q34;q32)'''
|}
|Rare (<5%; single-case report<ref>{{Cite journal|last=Fujimoto|first=Rika|last2=Ozawa|first2=Tatsuhiko|last3=Itoyama|first3=Takahiro|last4=Sadamori|first4=Naoki|last5=Kurosawa|first5=Nobuyuki|last6=Isobe|first6=Masaharu|date=2012|title=HELIOS-BCL11B fusion gene involvement in a t(2;14)(q34;q32) in an adult T-cell leukemia patient|url=https://pubmed.ncbi.nlm.nih.gov/22867996|journal=Cancer Genetics|volume=205|issue=7-8|pages=356–364|doi=10.1016/j.cancergen.2012.04.006|issn=2210-7762|pmid=22867996}}</ref>)
|
<blockquote class="blockedit">
|No
<center><span style="color:Maroon">'''End of V4 Section'''</span>
|
----
|}
</blockquote>
 
 
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}</blockquote>
 
ATLL diagnosis can be made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL). Diagnosis can also be made by quantifying proviral DNA loads (PVLs) in peripheral blood mononuclear cells using real time PCR. PVL of an infected person can range from 0.01 to 50% or higher. Other diagnostic criteria includes appropriate patient demographic information, hypercalcemia, skin lesions and a leukemic phase.
 
The prognosis of ATLL is largely dependent on the subtype. The acute and lymphomatous subtypes are aggressive, with a median survival of 6.2 months and 10.2 months, respectively. The less-aggressive chronic and smoldering subtypes have a median survival of approximately 4.5 years<ref name=":3">{{Cite journal|last=Shimoyama|first=M.|date=1991-11|title=Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)|url=https://pubmed.ncbi.nlm.nih.gov/1751370|journal=British Journal of Haematology|volume=79|issue=3|pages=428–437|doi=10.1111/j.1365-2141.1991.tb08051.x|issn=0007-1048|pmid=1751370}}</ref>. Prognostic factors include clinical variant, age, serum calcium and LDH levels as well as detection of opportunistic infections of parasitic or viral types and p16 gene deletion and p53 mutation.
 
As ATLL is resistant to most chemotherapy, there is no standard chemotherapy regimen. High dose combination chemotherapy and bone marrow transplantation have been tried previously<ref>{{Cite journal|last=Hishizawa|first=Masakatsu|last2=Kanda|first2=Junya|last3=Utsunomiya|first3=Atae|last4=Taniguchi|first4=Shuichi|last5=Eto|first5=Tetsuya|last6=Moriuchi|first6=Yukiyoshi|last7=Tanosaki|first7=Ryuji|last8=Kawano|first8=Fumio|last9=Miyazaki|first9=Yasushi|date=2010-08-26|title=Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study|url=https://pubmed.ncbi.nlm.nih.gov/20479287|journal=Blood|volume=116|issue=8|pages=1369–1376|doi=10.1182/blood-2009-10-247510|issn=1528-0020|pmid=20479287}}</ref>. Monoclonal antibody-based therapies against IL-2R (anti-Tac), CCR4 (mogamulizumab) and CD52 (alemtuzumab) have also been attempted along with arsenic trioxide, interferon α and zidovudine<ref>{{Cite journal|last=Hermine|first=Olivier|last2=Ramos|first2=Juan Carlos|last3=Tobinai|first3=Kensei|date=02 2018|title=A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies|url=https://pubmed.ncbi.nlm.nih.gov/29411267|journal=Advances in Therapy|volume=35|issue=2|pages=135–152|doi=10.1007/s12325-018-0658-4|issn=1865-8652|pmc=5818559|pmid=29411267}}</ref>.
 
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==


 
ATLL with high number of chromosomal imbalances is associated with poor survival<ref>{{Cite journal|last=Itoyama|first=T.|last2=Chaganti|first2=R. S.|last3=Yamada|first3=Y.|last4=Tsukasaki|first4=K.|last5=Atogami|first5=S.|last6=Nakamura|first6=H.|last7=Tomonaga|first7=M.|last8=Ohshima|first8=K.|last9=Kikuchi|first9=M.|date=2001-06-01|title=Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki|url=https://pubmed.ncbi.nlm.nih.gov/11369658|journal=Blood|volume=97|issue=11|pages=3612–3620|doi=10.1182/blood.v97.11.3612|issn=0006-4971|pmid=11369658}}</ref><ref name=":3">{{Cite journal|last=Tsukasaki|first=K.|last2=Krebs|first2=J.|last3=Nagai|first3=K.|last4=Tomonaga|first4=M.|last5=Koeffler|first5=H. P.|last6=Bartram|first6=C. R.|last7=Jauch|first7=A.|date=2001-06-15|title=Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course|url=https://pubmed.ncbi.nlm.nih.gov/11389029|journal=Blood|volume=97|issue=12|pages=3875–3881|doi=10.1182/blood.v97.12.3875|issn=0006-4971|pmid=11389029}}</ref><ref name=":0">{{Cite journal|last=Oshiro|first=Aya|last2=Tagawa|first2=Hiroyuki|last3=Ohshima|first3=Koichi|last4=Karube|first4=Kennosuke|last5=Uike|first5=Naokuni|last6=Tashiro|first6=Yukie|last7=Utsunomiya|first7=Atae|last8=Masuda|first8=Masato|last9=Takasu|first9=Nobuyuki|date=2006-06-01|title=Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16484591|journal=Blood|volume=107|issue=11|pages=4500–4507|doi=10.1182/blood-2005-09-3801|issn=0006-4971|pmid=16484591}}</ref><ref name=":2">{{Cite journal|last=Kataoka|first=Keisuke|last2=Iwanaga|first2=Masako|last3=Yasunaga|first3=Jun-Ichirou|last4=Nagata|first4=Yasunobu|last5=Kitanaka|first5=Akira|last6=Kameda|first6=Takuro|last7=Yoshimitsu|first7=Makoto|last8=Shiraishi|first8=Yuichi|last9=Sato-Otsubo|first9=Aiko|date=01 11, 2018|title=Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29084771|journal=Blood|volume=131|issue=2|pages=215–225|doi=10.1182/blood-2017-01-761874|issn=1528-0020|pmc=5757690|pmid=29084771}}</ref>.
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|1
|Amp
|1p36
|''H6PD, VPS13D, PRDM2''
|
|
|No
|
|
|
|
|
|
|
|}
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
ATLL with high number of chromosomal imbalances is associated with poor survival<ref>{{Cite journal|last=Itoyama|first=T.|last2=Chaganti|first2=R. S.|last3=Yamada|first3=Y.|last4=Tsukasaki|first4=K.|last5=Atogami|first5=S.|last6=Nakamura|first6=H.|last7=Tomonaga|first7=M.|last8=Ohshima|first8=K.|last9=Kikuchi|first9=M.|date=2001-06-01|title=Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki|url=https://pubmed.ncbi.nlm.nih.gov/11369658|journal=Blood|volume=97|issue=11|pages=3612–3620|doi=10.1182/blood.v97.11.3612|issn=0006-4971|pmid=11369658}}</ref><ref>{{Cite journal|last=Tsukasaki|first=K.|last2=Krebs|first2=J.|last3=Nagai|first3=K.|last4=Tomonaga|first4=M.|last5=Koeffler|first5=H. P.|last6=Bartram|first6=C. R.|last7=Jauch|first7=A.|date=2001-06-15|title=Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course|url=https://pubmed.ncbi.nlm.nih.gov/11389029|journal=Blood|volume=97|issue=12|pages=3875–3881|doi=10.1182/blood.v97.12.3875|issn=0006-4971|pmid=11389029}}</ref><ref>{{Cite journal|last=Oshiro|first=Aya|last2=Tagawa|first2=Hiroyuki|last3=Ohshima|first3=Koichi|last4=Karube|first4=Kennosuke|last5=Uike|first5=Naokuni|last6=Tashiro|first6=Yukie|last7=Utsunomiya|first7=Atae|last8=Masuda|first8=Masato|last9=Takasu|first9=Nobuyuki|date=2006-06-01|title=Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16484591|journal=Blood|volume=107|issue=11|pages=4500–4507|doi=10.1182/blood-2005-09-3801|issn=0006-4971|pmid=16484591}}</ref><ref name=":2">{{Cite journal|last=Kataoka|first=Keisuke|last2=Iwanaga|first2=Masako|last3=Yasunaga|first3=Jun-Ichirou|last4=Nagata|first4=Yasunobu|last5=Kitanaka|first5=Akira|last6=Kameda|first6=Takuro|last7=Yoshimitsu|first7=Makoto|last8=Shiraishi|first8=Yuichi|last9=Sato-Otsubo|first9=Aiko|date=01 11, 2018|title=Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29084771|journal=Blood|volume=131|issue=2|pages=215–225|doi=10.1182/blood-2017-01-761874|issn=1528-0020|pmc=5757690|pmid=29084771}}</ref>.
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|-
|1
|1
|Gain
|Gain
|1q
|1q
|Multiple candidates
|
|No
|1q gains common in lymphoma-type ATLL<ref name=":0" />
|-
|-
|2
|2
|Gain
|Gain
|2p
|2p
|''BCL11A, REL''
|
|No
|
|-
|-
|3
|3
|Gain
|Gain
|3p
|3p
|
|
|No
|
|-
|-
|4
|4
|Gain
|Gain
|4q
|4q
|
|
|No
|
|-
|-
|6
|6
|Loss
|Loss
|6q
|6q
|
|
|No
|
|-
|-
|7
|7
|Gain
|Gain
|7p, 7q
|7p, 7q
|
|
|No
|
|-
|9
|Loss/homozygous deletion
|9p21.3
|''CDKN2A/B''
|P
|No
|More common in aggressive  (acute/lymphoma) subtypes
|-
|-
|9
|9
|Amp
|Amp
|9p
|9p24.1; chr9:5,450,542–5,470,554  [GRCh38; ~20 kb]
|''PD-L1'' (''CD274'')
|P
|No
|9p24.1 amplifications of ''PD-L1''  predict worse prognosis in both indolent and aggressive ATLL; more common in  aggressive (acute/lymphoma) subtypes; included in multivariate risk model
|-
|-
|10
|10
|Loss
|Loss
|10p
|10p
|
|
|No
|
|-
|-
|13
|13
|Loss
|Loss
|13q
|13q32
|''GPR183''
|
|No
|More frequent in older patients
|-
|-
|14
|14
|Gain
|Gain
|14q
|14q32<ref name=":0" /><ref name=":3" />
|
|
|No
|
|-
|-
|16
|16
|Loss
|Loss
|16q
|16q23
|''WWOX''
|
|No
|
|-
|-
|18
|18
|Loss
|Loss
|18p
|18p
|}
|
|
<blockquote class="blockedit">
|
<center><span style="color:Maroon">'''End of V4 Section'''</span>
|
----
|}
</blockquote>
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==


Cytogenetic studies show that ATLL ofte<ref name=":1" />n has a complex abnormal karyotype without a single distinct abnormality. Observed recurrent abnormalities include trisomy for 3, 7 or 21 and monosomy for X as well as deletion of Y and abnormalities of chromosome 6 and 14. Chromosome 14 rearrangements involving TCRA and TCRD at 14q11 and TCL1 at 14q32 have been documented<ref>{{Cite journal|date=1987-11|title=Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Fifth International Workshop on Chromosomes in Leukemia-Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/2889485|journal=Blood|volume=70|issue=5|pages=1554–1564|issn=0006-4971|pmid=2889485}}</ref>. Frequent deletions in known fragile sites have been detected in over 500 patients.
Cytogenetic studies show that ATLL often<ref name=":1">{{Cite journal|last=Kataoka|first=Keisuke|last2=Nagata|first2=Yasunobu|last3=Kitanaka|first3=Akira|last4=Shiraishi|first4=Yuichi|last5=Shimamura|first5=Teppei|last6=Yasunaga|first6=Jun-Ichirou|last7=Totoki|first7=Yasushi|last8=Chiba|first8=Kenichi|last9=Sato-Otsubo|first9=Aiko|date=2015-11|title=Integrated molecular analysis of adult T cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26437031|journal=Nature Genetics|volume=47|issue=11|pages=1304–1315|doi=10.1038/ng.3415|issn=1546-1718|pmid=26437031}}</ref> has a complex abnormal karyotype without a single distinct abnormality. Observed recurrent abnormalities include trisomy for 3, 7 or 21 and monosomy for X as well as deletion of Y and abnormalities of chromosome 6 and 14. Chromosome 14 rearrangements involving TCRA and TCRD at 14q11 and TCL1 at 14q32 have been documented<ref>{{Cite journal|date=1987-11|title=Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Fifth International Workshop on Chromosomes in Leukemia-Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/2889485|journal=Blood|volume=70|issue=5|pages=1554–1564|issn=0006-4971|pmid=2889485}}</ref>. Frequent deletions in known fragile sites have been detected in over 500 patients.
{| class="wikitable sortable"
{| class="wikitable sortable"
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|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Trisomy 3, 7 or 21
Co-deletion of 1p and 18q
|
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|
|
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Monosomy X
Microsatellite instability - hypermutated
|
|
|
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|
|
|-
|-
|Deletion Y
|
|
|
|
|
|-
|Abnormalities of chromosome 6 and 14
|
|
|
|
|
|-
|
|
|
|
|
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|
|
|}<center><span style="color:Maroon">'''End of V4 Section'''</span>
|}<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
==Epigenomic Alterations==
Epigenetic alterations also result in dysregulated TCR/NF-κB signaling in ATLL. DNA hypermethylation of CpG islands is detected in 1/3<sup>rd</sup> of all ATLL patients. As a result, genes involved in Cys2-His2 (C2H2) zinc finger genes and those encoding MHC class I molecules are silenced<ref name=":1" />.


ATLL patients have high expression of polycomb repressive complex (PRC) 2 components like EZH2, its homolog EZH1 and H3K27 methylase causing accumulation of trimethylation of H3K27 and altering the expression of over half of the genes. The severity of the disease is linked to continued down regulation of genes<ref>{{Cite journal|last=Fujikawa|first=Dai|last2=Nakagawa|first2=Shota|last3=Hori|first3=Makoto|last4=Kurokawa|first4=Naoya|last5=Soejima|first5=Ai|last6=Nakano|first6=Kazumi|last7=Yamochi|first7=Tadanori|last8=Nakashima|first8=Makoto|last9=Kobayashi|first9=Seiichiro|date=2016-04-07|title=Polycomb-dependent epigenetic landscape in adult T-cell leukemia|url=https://pubmed.ncbi.nlm.nih.gov/26773042|journal=Blood|volume=127|issue=14|pages=1790–1802|doi=10.1182/blood-2015-08-662593|issn=1528-0020|pmid=26773042}}</ref>.  
== Epigenomic Alterations ==
Epigenetic alterations also result in dysregulated TCR/NF-κB signaling in ATLL. DNA hypermethylation of CpG islands is detected in 1/3<sup>rd</sup> of all ATLL patients. As a result, genes involved in Cys2-His2 (C2H2) zinc finger genes and those encoding MHC class I molecules are silenced<ref name=":1" />.


==Genes and Main Pathways Involved==
ATLL patients have high expression of polycomb repressive complex (PRC) 2 components like EZH2, its homolog EZH1 and H3K27 methylase causing accumulation of trimethylation of H3K27 and altering the expression of over half of the genes. The severity of the disease is linked to continued down regulation of genes<ref>{{Cite journal|last=Fujikawa|first=Dai|last2=Nakagawa|first2=Shota|last3=Hori|first3=Makoto|last4=Kurokawa|first4=Naoya|last5=Soejima|first5=Ai|last6=Nakano|first6=Kazumi|last7=Yamochi|first7=Tadanori|last8=Nakashima|first8=Makoto|last9=Kobayashi|first9=Seiichiro|date=2016-04-07|title=Polycomb-dependent epigenetic landscape in adult T-cell leukemia|url=https://pubmed.ncbi.nlm.nih.gov/26773042|journal=Blood|volume=127|issue=14|pages=1790–1802|doi=10.1182/blood-2015-08-662593|issn=1528-0020|pmid=26773042}}</ref>.


== Genes and Main Pathways Involved ==
The most important genes involved in the development and progress of ATLL are the Tax and HBZ contributed by the HTLV-1 virus and genes listed in gene mutations table (above) from the host. The main pathways involved are TCR-NF-κB signaling by gain of function and amplifications in PLCG1, VAV1 and FYN, CD28, PRKCB, CARD11, IRF4 and RHOA; and loss of function mutations or deletions in CBLB, TRAF, TNFAIP3 and CSNK1A1<ref name=":1" />.
The most important genes involved in the development and progress of ATLL are the Tax and HBZ contributed by the HTLV-1 virus and genes listed in gene mutations table (above) from the host. The main pathways involved are TCR-NF-κB signaling by gain of function and amplifications in PLCG1, VAV1 and FYN, CD28, PRKCB, CARD11, IRF4 and RHOA; and loss of function mutations or deletions in CBLB, TRAF, TNFAIP3 and CSNK1A1<ref name=":1" />.


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Chemokine receptors including CCR4 and CCR7 are responsible for the infiltration of neoplastic cells into other organs along with activation of PI3K/AKT signaling.
Chemokine receptors including CCR4 and CCR7 are responsible for the infiltration of neoplastic cells into other organs along with activation of PI3K/AKT signaling.


The epigenetic mechanism is also exploited to alter gene expression and promote ATLL progression as explained above.
The epigenetic mechanism is also exploited to alter gene expression and promote ATLL progression as explained above<center><center>
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|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
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==Genetic Diagnostic Testing Methods==


== Genetic Diagnostic Testing Method ==
Initial diagnosis of ATLL should include a comprehensive physical exam with skin evaluation and CT scans of the chest, abdomen and pelvis. The laboratory evaluation should include: a complete blood count (CBC), metabolic panel (serum electrolyte levels, calcium, creatinine and blood urea nitrogen) and serum LDH levels. Testing methods including PCR, Flow Cytometry, ELISA, serology, and immunohistochemistry in addition to morphologic studies may be employed to diagnose ATLL<ref name=":4">NCCN Clinical Practice Guidelines in Oncology, T-Cell Lymphomas, Version 1.2021. Available at NCCN.org.</ref>.
Initial diagnosis of ATLL should include a comprehensive physical exam with skin evaluation and CT scans of the chest, abdomen and pelvis. The laboratory evaluation should include: a complete blood count (CBC), metabolic panel (serum electrolyte levels, calcium, creatinine and blood urea nitrogen) and serum LDH levels. Testing methods including PCR, Flow Cytometry, ELISA, serology, and immunohistochemistry in addition to morphologic studies may be employed to diagnose ATLL<ref name=":4">NCCN Clinical Practice Guidelines in Oncology, T-Cell Lymphomas, Version 1.2021. Available at NCCN.org.</ref>.


==Familial Forms==
== Familial Forms ==
 
 
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Additional Information==


== Additional Information ==
Put your text here
Put your text here


==Links==
== Links ==
 
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Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
== References ==
==References==
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==Notes==
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.


Prior Author(s):
Prior Author(s):  
 
Prasad R. Kopparapu, PhD and Ferrin C. Wheeler, PhD, FACMG
 


       
<nowiki>*</nowiki>''Citation of this Page'': “Adult T-cell leukaemia/lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Adult_T-cell_leukaemia/lymphoma</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Adult T-cell leukaemia/lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Adult_T-cell_leukaemia/lymphoma</nowiki>.
[[Category:HAEM5]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases A]]
[[Category:Diseases A]]
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