T-cell Large Granular Lymphocytic Leukemia

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editPREVIOUS EDITION
This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

  • Michelle Don, MD, MS

Cancer Category

Cancer Sub-Classification / Subtype

  • T-cell Large Granular Lymphocytic Leukemia (T-LGLL leukemia)

Definition / Description of Disease[1]

  • Increased peripheral blood large granular lymphocytes (LGLs) for >6 months without a identifiable cause
  • Chronic and often indolent T-cell proliferation

Synonyms / Terminology

  • T-cell large granular lymphocytic leukemia

Epidemiology / Prevalence[1]

  • 2-3% of mature small lymphocytic leukemias
  • Male:Female ~ 1:1
  • Most commonly occurs between ages 45-75 years old

Clinical Features[1]

  • Severe neutropenia
  • Lymphocyte count usually 2-20x109/L
  • Has been reported to occur with:
    • Severe red cell hypoplasia
    • Rheumatoid arthritis
    • Low grade B-cell malignancies

Sites of Involvement[1]

  • Peripheral blood and bone marrow
  • Spleen - infiltration and expansion of red pulp
  • Liver
  • Skin (rare)
  • Lymph nodes (exceptional)

Morphologic Features

Large granular lymphocytes

  • Moderate to abundant cytoplasm
  • Fine or course azurophilic granules

Immunophenotype[1]

Finding Marker
Positive CD8, CD2, CD3, CD16, CD57, αβ (alpha-beta) TCR

Cytotoxic effector proteins: TIA1, Granzyme B, Granzyme M

Negative CD4, CD5, CD7
Please note:
  • Cases of CD4+ LGL leukemia has been described[2]
  • Cases of CD4-/CD8-, γδ (gamma-delta) T-LGL leukemia has also been described (<5% of cases)[3]

Chromosomal Rearrangements (Gene Fusions)

  • No known chromosomal rearrangements

Characteristic Chromosomal Aberrations / Patterns

  • No characteristic chromosomal aberrations have been identified
  • Unique cytogenetic findings include: (reported in one case report of γδ variant T-cell LGL)[4]
    • Interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN‐LOH located at 17q[4]

Genomic Gain/Loss/LOH

  • No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in few cases[5]

Gene Mutations (SNV/INDEL)

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

Gene* Mutation Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence Additional information
STAT3
  • Src-like homologue 2 (SH2) domain of STAT3
  • Most frequently affecting codons Y640 or D661[1]
    • Also affecting:
  • Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT3 in vitro[7][8]
 GOF 40-70%[8]
  • 17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.[9]
  • Take caution as STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma[10]
STAT5B
  • Src-like homologue 2 (SH2) domain of STAT5
  • Including: N642H mutation (associated with more aggressive disease)[11][12]
  • Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT5B in vitro[7][8]
 GOF 2%[11]
TNFAIP3
  • Somatic mutations[6]
    • Y353X
    • K354K
    • Q741Q
    • E630X
    • A717T
    • F127C
 LOF (Nonsense mutations)[6] Identified in 3/39 patients[6]
  • In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (p  = 0.004)[6]
  • TNFAIP3 itself is a NF‐κB target gene[13]

*More comprehensive listing of specific mutations in these genes can be found elsewhere (COSMIC, cBioPortal)

Epigenomics (Methylation)

  • Epigenetic inactivation of JAK/STAT pathway inhibitors
    • SOCS3 has a crucial role in regulating STAT3 activation[14]
    • An epigenetic inhibition mechanism to SOCS3 gene is hypothesized[14]
    • KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter[14]


Genes and Main Pathways Involved

  • JAK/STAT[5]
    • Constitutive activation
  • NK-κB[5]
    • Activation of this pathway
    • Preventing apoptosis
  • T-LGL's express high levels of FAS and FASL[5]
    • Resistant to FAS mediated apoptosis
    • Leading to activation of prosurvival pathways
    • Postulated to lead to neutropenia seen in these patients.
  • RAS/RAF1/MEK1/ERK [5]
    • Overactive RAS
    • Constitutive activation of RAS and ERK
  • PI3K/AKT[5]
    • Dysregulation
    • Contributing to apoptosis inhibition

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[1]
      • 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[5]
      • Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL[5]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • There are no FDA approved targeted therapies for T-LGL
  • STAT3 mutations can be used to follow-up, in response to treatment[9]
    • Take caution as STAT mutations are not specific to T-LGL and can be seen in other T-cell lymphomas
  • STAT3 mutation, Y640F, has a predicted response to initial therapy with methotrexate[15]
  • Bortezomib is considered due to NF-κB constitutive activity in T-LGL leukemia[16]

Familial Forms

  • No known familiar forms as of yet.

Other Information

  • N/A

Links

References

(use "Cite" icon at top of page)

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Chan W.C., et al., (2017). T-cell large granular lymphocytic leukemia, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p 348-350.
  2. ↑ Lima M, Almeida J, dos Anjos Teixeira M, del Carmen Alguero M, Santos AH, Balanzategui A, Queirós ML, Bárcena P, Izarra A, Fonseca S, Bueno C. TCRαβ+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder. The American journal of pathology. 2003 Aug 1;163(2):763-71.
  3. ↑ Chen YH, Chadburn A, Evens AM, Winter JN, Gordon LI, Chenn A, Goolsby C, Peterson L. Clinical, morphologic, immunophenotypic, and molecular cytogenetic assessment of CD4–/CD8–γδ T-cell large granular lymphocytic leukemia. American journal of clinical pathology. 2011 Aug 1;136(2):289-99.
  4. ↑ 4.0 4.1 Zhang L, Ramchandren R, Papenhausen P, Loughran TP, Sokol L. Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11. 2q25. 3 and additional aberrations. European journal of haematology. 2014 Sep;93(3):260-4.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-94.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Johansson P, Bergmann A, Rahmann S, Wohlers I, Scholtysik R, Przekopowitz M, Seifert M, Tschurtschenthaler G, Webersinke G, Jäger U, Siebert R. Recurrent alterations of TNFAIP 3 (A 20) in T‐cell large granular lymphocytic leukemia. International journal of cancer. 2016 Jan 1;138(1):121-4.
  7. ↑ 7.0 7.1 Jerez A, Clemente MJ, Makishima H, Koskela H, LeBlanc F, Peng Ng K, Olson T, Przychodzen B, Afable M, Gomez-Segui I, Guinta K. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood, The Journal of the American Society of Hematology. 2012 Oct 11;120(15):3048-57.
  8. ↑ 8.0 8.1 8.2 Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, Majumder MM. Somatic STAT3 mutations in large granular lymphocytic leukemia. New England Journal of Medicine. 2012 May 17;366(20):1905-13.
  9. ↑ 9.0 9.1 Rajala HL, Olson T, Clemente MJ, Lagström S, Ellonen P, Lundan T, Hamm DE, Zaman SA, Marti JM, Andersson EI, Jerez A. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. haematologica. 2015 Jan 1;100(1):91-9.
  10. ↑ 10.0 10.1 Yabe M, Medeiros LJ, Wang SA, Tang G, Bueso-Ramos CE, Jorgensen JL, Bhagat G, Chen W, Li S, Young KH, Miranda RN. Distinguishing between hepatosplenic T-cell lymphoma and γδ T-cell large granular lymphocytic leukemia. The American journal of surgical pathology. 2017 Jan 1;41(1):82-93.
  11. ↑ 11.0 11.1 Rajala HL, Eldfors S, Kuusanmäki H, Van Adrichem AJ, Olson T, Lagström S, Andersson EI, Jerez A, Clemente MJ, Yan Y, Zhang D. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood, The Journal of the American Society of Hematology. 2013 May 30;121(22):4541-50.
  12. ↑ 12.0 12.1 Rajala HL, Porkka K, Maciejewski JP, Loughran Jr TP, Mustjoki S. Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations. Annals of Medicine. 2014 May 1;46(3):114-22.
  13. ↑ Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, Albert R, Loughran TP. Network model of survival signaling in large granular lymphocyte leukemia. Proceedings of the National Academy of Sciences. 2008 Oct 21;105(42):16308-13.
  14. ↑ 14.0 14.1 14.2 Teramo, Antonella; et al. (2013-05-09). "Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia". Blood. 121 (19): 3843–3854, S1. doi:10.1182/blood-2012-07-441378. ISSN 1528-0020. PMID 23515927.
  15. ↑ Loughran TP, Zickl L, Olson TL, Wang V, Zhang D, Rajala HL, Hasanali Z, Bennett JM, Lazarus HM, Litzow MR, Evens AM. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia. 2015 Apr;29(4):886-94.
  16. ↑ Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, Yang X. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer cell. 2012 Nov 13;22(5):645-55.

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