Adult T-cell leukaemia/lymphoma
Haematolymphoid Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
Primary Author(s)*
Sumire Kitahara, MD
Cedars-Sinai Medical Center, Los Angeles, CA
WHO Classification of Disease
| Structure | 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)
Smouldering ATLL Chronic ATLL Lymphoma ATLL Acute ATLL |
Related Terminology
| Acceptable | Adult T-cell leukaemia/lymphoma, HTLV-1 associated |
| Not Recommended | N/A |
Gene Rearrangements
| 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) | 3′-UTR–truncating structural variants (no protein fusion)[1] | 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 | No | Highlights immune-evasion axis and immune checkpoint biology, but PD-1 blockade has shown harm and induced rapid progression in ATLL[2] |
| REL (c-Rel) | 3′ truncations (no partner gene; gain-of-function)[3] | 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 | ||
| CD28 | CTLA4::CD28
ICOS::CD28 |
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%[4]) | T | No | Potential for CTLA4 blockade as treatment when CD28 fusions are present |
| BCL11B | HELIOS (IKZF2)::BCL11B | Transcription-factor fusion likely deregulates T-cell developmental programs | t(2;14)(q34;q32) | Rare (<5%; single-case report[5]) | No |
Individual Region Genomic Gain/Loss/LOH
ATLL with high number of chromosomal imbalances is associated with poor survival[6][7][8][9].
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| 1 | Amp | 1p36 | H6PD, VPS13D, PRDM2 | No | ||
| 1 | Gain | 1q | Multiple candidates | No | 1q gains common in lymphoma-type ATLL[8] | |
| 2 | Gain | 2p | BCL11A, REL | No | ||
| 3 | Gain | 3p | No | |||
| 4 | Gain | 4q | No | |||
| 6 | Loss | 6q | No | |||
| 7 | Gain | 7p, 7q | No | |||
| 9 | Loss/homozygous deletion | 9p21.3 | CDKN2A/B | P | No | More common in aggressive (acute/lymphoma) subtypes |
| 9 | Amp | 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 | Loss | 10p | No | |||
| 13 | Loss | 13q32 | GPR183 | No | More frequent in older patients | |
| 14 | Gain | 14q32[8][7] | No | |||
| 16 | Loss | 16q23 | WWOX | No | ||
| 18 | Loss | 18p |
Characteristic Chromosomal or Other Global Mutational Patterns
Cytogenetic studies show that ATLL often[10] 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[11]. Frequent deletions in known fragile sites have been detected in over 500 patients.
| Chromosomal Pattern | Molecular Pathogenesis | 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 |
|---|---|---|---|---|---|
| Trisomy 3, 7 or 21 | |||||
| Monosomy X | |||||
| Deletion Y | |||||
| Abnormalities of chromosome 6 and 14 | |||||
Gene Mutations (SNV/INDEL)
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[12][9][13].
| 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 |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: 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). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.
| Gene | Mutation | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|---|
| PLCG1 | TCR – NF-κB Signaling | GOF | ||
| PKCB | TCR – NF-κB Signaling | GOF | ||
| CARD11 | TCR – NF-κB Signaling | GOF | ||
| VAV1 | TCR – NF-κB Signaling | GOF | ||
| CD237 | TCR – NF-κB Signaling | GOF | ||
| RHOA | RAS-RAF-ERK pathway | GOF | ||
| IRF4 | Transcription Factor | GOF | ||
| NOTCH1 | Transcription Factor | GOF | ||
| FBXW7 | Transcription Factor | GOF | ||
| STAT3 | Transcription Factor | GOF | ||
| TNFAIP3/A20 | TCR – NF-κB Signaling | LOF | ||
| NFKBIA/IκBα | TCR – NF-κB Signaling | LOF | ||
| TRAF3 | TCR – NF-κB Signaling | LOF | ||
| CBLB | TCR – NF-κB Signaling | LOF | ||
| TP53 | Tumor Suppressor | LOF | ||
| CDKN2 | Tumor Suppressor | LOF | ||
| GATA3 | Transcription Factor | LOF | ||
| EP300 | Transcription Factor | LOF | ||
| FAS | Apoptosis | LOF | ||
| WWOX | Apoptosis | LOF | ||
| HLA-B | Immune Surveillance | LOF | ||
| B2M | Immune Surveillance | LOF | ||
| PD-L1 | Immune Surveillance | Amplification |
Epigenomic Alterations
Epigenetic alterations also result in dysregulated TCR/NF-κB signaling in ATLL. DNA hypermethylation of CpG islands is detected in 1/3rd 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[10].
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[14].
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[10].
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
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[15].
Familial Forms
Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)
Additional Information
Put your text here
Links
Put a link here or anywhere appropriate in this page (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 "http://www." portion.)
References
- ↑ Kataoka, Keisuke; et al. (2016-06-16). "Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers". Nature. 534 (7607): 402–406. doi:10.1038/nature18294. ISSN 1476-4687. PMID 27281199.
- ↑ Rauch, Daniel A.; et al. (2019-10-24). "Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade". Blood. 134 (17): 1406–1414. doi:10.1182/blood.2019002038. ISSN 1528-0020. PMC 6839957. PMID 31467059.
- ↑ Kogure, Yasunori; et al. (2022-02-17). "Whole-genome landscape of adult T-cell leukemia/lymphoma". Blood. 139 (7): 967–982. doi:10.1182/blood.2021013568. ISSN 0006-4971. PMC 8854674 Check
|pmc=value (help). PMID 34695199 Check|pmid=value (help). - ↑ Yoshida, Noriaki; et al. (2020-04-23). "Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions". Blood. 135 (17): 1467–1471. doi:10.1182/blood.2019001815. ISSN 1528-0020. PMC 7180081 Check
|pmc=value (help). PMID 31961925. - ↑ Fujimoto, Rika; et al. (2012). "HELIOS-BCL11B fusion gene involvement in a t(2;14)(q34;q32) in an adult T-cell leukemia patient". Cancer Genetics. 205 (7–8): 356–364. doi:10.1016/j.cancergen.2012.04.006. ISSN 2210-7762. PMID 22867996.
- ↑ Itoyama, T.; et al. (2001-06-01). "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". Blood. 97 (11): 3612–3620. doi:10.1182/blood.v97.11.3612. ISSN 0006-4971. PMID 11369658.
- ↑ 7.0 7.1 Tsukasaki, K.; et al. (2001-06-15). "Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course". Blood. 97 (12): 3875–3881. doi:10.1182/blood.v97.12.3875. ISSN 0006-4971. PMID 11389029.
- ↑ 8.0 8.1 8.2 Oshiro, Aya; et al. (2006-06-01). "Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma". Blood. 107 (11): 4500–4507. doi:10.1182/blood-2005-09-3801. ISSN 0006-4971. PMID 16484591.
- ↑ 9.0 9.1 Kataoka, Keisuke; et al. (01 11, 2018). "Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma". Blood. 131 (2): 215–225. doi:10.1182/blood-2017-01-761874. ISSN 1528-0020. PMC 5757690. PMID 29084771. Check date values in:
|date=(help) - ↑ 10.0 10.1 10.2 Kataoka, Keisuke; et al. (2015-11). "Integrated molecular analysis of adult T cell leukemia/lymphoma". Nature Genetics. 47 (11): 1304–1315. doi:10.1038/ng.3415. ISSN 1546-1718. PMID 26437031. Check date values in:
|date=(help) - ↑ "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". Blood. 70 (5): 1554–1564. 1987-11. ISSN 0006-4971. PMID 2889485. Check date values in:
|date=(help) - ↑ Kogure, Yasunori; et al. (2017-09). "Genetic alterations in adult T-cell leukemia/lymphoma". Cancer Science. 108 (9): 1719–1725. doi:10.1111/cas.13303. ISSN 1349-7006. PMC 5581529. PMID 28627735. Check date values in:
|date=(help) - ↑ Kataoka, Keisuke; et al. (2015-11). "Integrated molecular analysis of adult T cell leukemia/lymphoma". Nature Genetics. 47 (11): 1304–1315. doi:10.1038/ng.3415. ISSN 1546-1718. PMID 26437031. Check date values in:
|date=(help) - ↑ Fujikawa, Dai; et al. (2016-04-07). "Polycomb-dependent epigenetic landscape in adult T-cell leukemia". Blood. 127 (14): 1790–1802. doi:10.1182/blood-2015-08-662593. ISSN 1528-0020. PMID 26773042.
- ↑ NCCN Clinical Practice Guidelines in Oncology, T-Cell Lymphomas, Version 1.2021. Available at NCCN.org.
Notes
*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 Associate Editor 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):
Prasad R. Kopparapu, PhD and Ferrin C. Wheeler, PhD, FACMG
*Citation of this Page: “Adult T-cell leukaemia/lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/6/2026, https://ccga.io/index.php/HAEM5:Adult_T-cell_leukaemia/lymphoma.