HAEM5:T-large granular lymphocytic leukaemia

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Nicolas LaScala, DO

Michelle Don, MD, MS

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)	T-large granular lymphocytic leukaemia

Related Terminology

Acceptable	T-cell lymphoproliferative disease of granular lymphocytes; T-cell large granular lymphocytic leukaemia
Not Recommended	T-cell large granular lymphocytosis; T-gamma lymphoproliferative disease

Gene Rearrangements

No know chromosomal 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
N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A

Individual Region Genomic Gain/Loss/LOH

No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.

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
N/A	N/A	N/A	N/A	N/A	N/A	N/A

Characteristic Chromosomal or Other Global Mutational Patterns

No characteristic chromosomal patterns have been identified.

One reported case with unique cytogenetic findings of a γδ variant T-cell LGL include: interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN-LOH, located at 17q.

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
N/A	N/A	N/A	N/A	N/A	N/A

Gene Mutations (SNV/INDEL)

Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.

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
STAT3	Gain of function in src-like homologue 2 (SH2) domain of STAT 3, frequently affecting codons Y640 or D661. Codons N647I,K658S, and K658F are also affected	Other	Common	D, P, T	WHO, NCCN	STAT3 mutation has been associated with statistically significant neutropenia, thrombocytopenia, and reduced numbers of most normal residual blood-leukocyte subsets STAT3 mutations are associated with a worse prognosis and reduced overall survival Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma 17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.
STAT5B	Gain of function src-like homologue 2 (SH2) domain of STAT5. Mutations include: N642H Y665F Q706L S715F T628S P685R V712E mutation of STAT5B is in the transactivation domain Mutations in the coiled-coil domain: CCD, Q220H Mutations in the DNA binding domain: DBD, E433G/K Mutations in the inter-domain region: P702A	Other	Rare	D,P,T	WHO, NCCN	N642H mutation (associated with more aggressive disease) Clones can acquire multiple STAT5B mutations STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma N642H mutation is associated with CD3+/CD56+ phenotype STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL
TNFAIP3	Loss of function Somatic mutations: Y353X K354K Q741 E630X A717T F127C	Other	Recurrent	P,T	WHO	TNFAIP 3 mutation has been correlated with increased overall survival TNFAIP3 itself is a NF‐κB target gene In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (p  = 0.004)
TET2	Loss of function	Other	Common	N/A	WHO	Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL
BCL11B	Missense H126R	Other	Rare	N/A	WHO	BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation.
FLT3	A high-impact Asp228Gly variant on JAK STAT has been demonstrated	Other	Rare	N/A	WHO	Connects STAT to the MAPK-Ras-ERK pathway and to IL-15
PTPN23	R641Q	Other	Rare	N/A	WHO	Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation
KMT2D	Loss of function	Other	Recurrent	N/A	None	Frequent co-occurrence of KMT2D and STAT3 mutations
TRAF3	c.650A>T p.E217V	Other	Rare	N/A	None	Mutated putative driver
CLIP3	c.908A>T p.D303V c.917A>T p.K306M	Other	Rare	N/A	None	Mutated putative driver
FBXW2	c.683C>G p.A228G	Other	Rare	N/A	None	Mutated putative driver
CREBBP	c.1178A>G p.N393S c.4306T>C p.C1436R	Other	Rare	N/A	None	Mutated putative driver
CCL2	SNV, somatic Mutation   P46R	Other	Rare	N/A	None	CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL

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.

Epigenomic Alterations

Epigenetic inactivation of JAK/STAT pathway inhibitors

• SOCS3 has a crucial role in regulating STAT3 activation
• An epigenetic inhibition mechanism to SOCS3 gene is hypothesized
• KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter
• Mutations in KMT2D and TET2 have been found to significantly co-occur with STAT3 mutations

Genes and Main Pathways Involved

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
JAK/STAT	Constitutive activation	Dysregulation of apoptosis
NK-kB	Pathway activation	Preventing apoptosis
FAS and FASL	Resistance to FAS mediated apoptosis	Activation of pro-survival pathways which is postulated to lead to neutropenia
RAS/RAF1/MEK1/ERK	Overactive RAS	Constitutive activation of RAS and ERK
PI3K/AKT	Dysregulation

Genetic Diagnostic Testing Methods

• Morphologic assessment, flow cytometry and immunohistochemistry
• PCR to assess for clonality, T-cell receptor (TCR) gene rearrangements
  • TCR gamma (TCRG) gene is rearranged in all cases, regardless of the type of TCR expressed, thus proves clonality
  • Can be helpful in differentiating a reactive lymphocytosis from clonal T-LGL's
    • NK LGL proliferations do not express TCR, making assessment of clonality difficult
    • Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL
• Myeloid neoplasms may present with clonal large granular lymphocyte expansion with STAT3/STAT5B mutations. Next generation sequencing can be diagnostically useful in these cases

Familial Forms

No known familiar forms as of yet.

Additional Information

PI3K-Akt has been found to be upregulated in KLRG1^- CD8⁺ T-LGLL. Studies are being conducted to examine treatment with linperlisib.

Myleoid clonal hematopoiesis is associated with the presence of cytopenia in LGLL

Links

Hepatosplenic T-cell lymphoma

Notes

*Citation of this Page: LaScala N, Don M“T-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/17/2026, https://ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia.

*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): N/A

Other Sections

Cancer Category

• Mature T- and NK-cell Neoplasm