HAEM5:Adult T-cell leukaemia/lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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)	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
REL (c-Rel)	3′ truncations (no partner gene; gain-of-function)	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%)	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)		No

Individual Region Genomic Gain/Loss/LOH

ATLL with high number of chromosomal imbalances is associated with poor survival.

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
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			No
16	Loss	16q23	WWOX		No
18	Loss	18p

Characteristic Chromosomal or Other Global Mutational Patterns

Cytogenetic studies show that ATLL often 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. 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.

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

End of V4 Section

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.

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.

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.

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.

Familial Forms

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Additional Information

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References

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.