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

 

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

Sumire Kitahara, MD

Cedars-Sinai Medical Center, Los Angeles, CA

==WHO Classification of Disease==

|Book

|Haematolymphoid Tumours (5th ed.)

|Category

|T-cell and NK-cell lymphoid proliferations and lymphomas

|Family

|Mature T-cell and NK-cell neoplasms

|Type

|Mature T-cell and NK-cell leukaemias

|Subtype(s)

|Adult T-cell leukaemia/lymphoma (ATLL)

|}

{| class="wikitable"

|Acceptable

|Adult T-cell leukaemia/lymphoma, HTLV-1 associated

|Not Recommended

|N/A

|}

!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)

!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

|''CD274 (PD-L1)''

|Loss of 3′-UTR microRNA regulation → PD-L1 overexpression → immune evasion

|Deletions, inversions, duplications, translocations at '''9p24.1''' disrupting 3′-UTR

|Common (≈20–25% of ATLL in large cohorts)

|T

|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>

|''REL (c-Rel)''

|C-terminal truncation removes negative-regulatory regions → transcription upregulation/activation of REL → NF-κB pathway activation

|'''2p16.1''' 3′-end truncating rearrangements

|Recurrent (~13%)

|

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>.

!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)

|9p24.1; chr9:5,450,542–5,470,554  [GRCh38; ~20 kb]

|13q32

|14q32<ref name=":0" /><ref name=":3" />

|16q23

|

==Characteristic Chromosomal or Other Global Mutational Patterns==

!Molecular Pathogenesis

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

|Deletion Y

|-

|Abnormalities of chromosome 6 and 14

|

|

|

|

Over 10% of ATLL cases harbor mostly gain of function mutations. ATLL harbors multiple recurrent mutations in genes involved in the TCR-NF-κB pathway, tumor suppressors, transcription factors involved in cell growth and proliferation, apoptosis, and immune surveillance<ref>{{Cite journal|last=Kogure|first=Yasunori|last2=Kataoka|first2=Keisuke|date=2017-09|title=Genetic alterations in adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/28627735|journal=Cancer Science|volume=108|issue=9|pages=1719–1725|doi=10.1111/cas.13303|issn=1349-7006|pmc=5581529|pmid=28627735}}</ref><ref name=":2" /><ref>{{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>.

!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

|<span class="blue-text">EXAMPLE:</span>''EGFR''

|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)

|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).

|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations

|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations

|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene

|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)

|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.

|<span class="blue-text">EXAMPLE:</span> Activating mutations

|<span class="blue-text">EXAMPLE:</span> Oncogene

|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>  

|}<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^rd 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>.

== Genes and Main Pathways Involved ==

Genes involving the immune surveillance program are also heavy altered to evade the immune response either by deletions in MHC class1 molecules, CD58, FAS or constitutive activation of PD-L1.

Genes involved in the Lymphocyte activation and differentiation(IRF4, GATA3, IKZF2) are also altered.

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<center><center>

<center>

|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations

|<span class="blue-text">EXAMPLE:</span> MAPK signaling

|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation

|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations

|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation

|<span class="blue-text">EXAMPLE:</span> Unregulated cell division

|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations

|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling

|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program

== Genetic Diagnostic Testing Method ==

== Familial Forms ==

Put your text here

== Links ==

==Notes==

Prior Author(s):  

Prasad R. Kopparapu, PhD and Ferrin C. Wheeler, PhD, FACMG

[[Category:HAEM5]]

[[Category:DISEASE]]

[[Category:Diseases A]]