Adult T-cell leukaemia/lymphoma
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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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
Put your text here and fill in the table (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.)
| 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 |
|---|---|---|---|---|---|---|---|
| EXAMPLE: ABL1 | EXAMPLE: BCR::ABL1 | EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: Common (CML) | EXAMPLE: D, P, T | EXAMPLE: Yes (WHO, NCCN) | EXAMPLE:
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference). |
| EXAMPLE: CIC | EXAMPLE: CIC::DUX4 | EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. | EXAMPLE: t(4;19)(q25;q13) | EXAMPLE: Common (CIC-rearranged sarcoma) | EXAMPLE: D | EXAMPLE:
DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references). | |
| EXAMPLE: ALK | EXAMPLE: ELM4::ALK
|
EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. | EXAMPLE: N/A | EXAMPLE: Rare (Lung adenocarcinoma) | EXAMPLE: T | EXAMPLE:
Both balanced and unbalanced forms are observed by FISH (add references). | |
| EXAMPLE: ABL1 | EXAMPLE: N/A | EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. | EXAMPLE: N/A | EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) | EXAMPLE: D, P, T | ||
| CD274 (PD-L1) | 3′-UTR–truncating structural variants (no protein fusion) | 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) | No | Highlights immune-evasion axis and immune checkpoint biology, but PD-1 blockade has shown harm and induced rapid progression in ATLL[1] |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.
Tandem duplications of 2q33.2 segments cause formation of CTLA4-CD28 and ICOS-CD28 fusion products that render prolonged co-stimulatory signals[2].
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence |
|---|---|---|---|
| 2q33.2 (Tandem Duplication) | 5’ CTLA/3’CD28 | der(2) | 7% |
| 2q33.2 (Tandem Duplication) | 5’ICOS/3’CD28 | der(2) | 7% |
End of V4 Section
editv4: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)
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[3]. 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[4]. 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[5].
End of V4 Section
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (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.)
| 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 |
|---|---|---|---|---|---|---|
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.
ATLL with high number of chromosomal imbalances is associated with poor survival[6][7][8][9].
| Chromosome Number | Gain/Loss/Amp/LOH | Region |
|---|---|---|
| 1 | Gain | 1q |
| 2 | Gain | 2p |
| 3 | Gain | 3p |
| 4 | Gain | 4q |
| 6 | Loss | 6q |
| 7 | Gain | 7p, 7q |
| 9 | Amp | 9p |
| 10 | Loss | 10p |
| 13 | Loss | 13q |
| 14 | Gain | 14q |
| 16 | Loss | 16q |
| 18 | Loss | 18p |
End of V4 Section
Characteristic Chromosomal or Other Global Mutational Patterns
Cytogenetic studies show that ATLL ofte[2]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[10]. 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 |
|---|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). | EXAMPLE: Common (Oligodendroglioma) | EXAMPLE: D, P | ||
| EXAMPLE:
Microsatellite instability - hypermutated |
EXAMPLE: Common (Endometrial carcinoma) | EXAMPLE: P, T | |||
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[11][9][12].
| 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[2].
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[13].
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[2].
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 Methods
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[14].
Familial Forms
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Additional Information
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References
- ↑ 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.
- ↑ 2.0 2.1 2.2 2.3 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) - ↑ Shimoyama, M. (1991-11). "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)". British Journal of Haematology. 79 (3): 428–437. doi:10.1111/j.1365-2141.1991.tb08051.x. ISSN 0007-1048. PMID 1751370. Check date values in:
|date=(help) - ↑ Hishizawa, Masakatsu; et al. (2010-08-26). "Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study". Blood. 116 (8): 1369–1376. doi:10.1182/blood-2009-10-247510. ISSN 1528-0020. PMID 20479287.
- ↑ Hermine, Olivier; et al. (02 2018). "A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies". Advances in Therapy. 35 (2): 135–152. doi:10.1007/s12325-018-0658-4. ISSN 1865-8652. PMC 5818559. PMID 29411267. Check date values in:
|date=(help) - ↑ 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.
- ↑ 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.
- ↑ 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) - ↑ "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
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Prior Author(s):
*Citation of this Page: “Adult T-cell leukaemia/lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/23/2025, https://ccga.io/index.php/HAEM5:Adult_T-cell_leukaemia/lymphoma.