Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009;9 Suppl 3(0 3):S244-53.
doi: 10.3816/CLM.2009.s.019.

Never say die: survival signaling in large granular lymphocyte leukemia

Mithun Vinod Shah  1 , Ranran Zhang, Thomas P Loughran Jr
Affiliations
Review

Never say die: survival signaling in large granular lymphocyte leukemia

Mithun Vinod Shah et al. Clin Lymphoma Myeloma. 2009.

Abstract

Large granular lymphocyte (LGL) leukemia is a rare disorder of mature cytotoxic T or natural killer cells. Large granular lymphocyte leukemia is characterized by the accumulation of cytotoxic cells in blood and infiltration in the bone marrow, liver, and spleen. Herein, we review clinical features of LGL leukemia. We focus our discussion on known survival signals believed to play a role in the pathogenesis of LGL leukemia and their potential therapeutic implications.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: All authors have no conflicts of interest.

Figures

Figure 1
Figure 1. MODEL OF APOPTOSIS-RESISTANCE IN LEUKEMIC LGL
Cytotoxic cells kill the _target cells by one of the two mechanisms. Activated cytotoxic cells upregulate FasL on their surfaces, while _target cells express Fas. This facilitates Fas-FasL mediated apoptosis in the _target cells (upper panel). Another mechanism is through exocytosis of cytolytic granules from CTL into the _target cells. Similar mechanism operates to maintain T-cell homeostasis. CTL use Fas-FasL mediated apoptosis to induce apoptosis either in self or another antigen-specific T-cells (middle panel). Leukemic LGL, despite expressing abundant Fas and FasL, are resistant to Fas-mediated apoptosis. It is believed that survival signaling overcomes Fas-mediated apoptotic signals in leukemic LGL leading to their accumulation (lower panel). CTL - cytotoxic T-lymphocyte; Mt. pathway – mitochondrial pathway.
Figure 2
Figure 2. SPHINGOLIPID RHEOSTAT AND ITS ROLE IN SURVIVAL OF LEUKEMIC LGL
Sphingolipid signaling is determined by balance between pro- and anti-apoptotic sphingolipid molecules. It is proposed that deregulation in sphingolipid signaling shifts the balance towards survival in leukemic LGL. NOE is an inhibitor of acid ceramidase (ASAH1), while SKI-I and II selectively inhibit sphingosine kinase (SPHK). FTY720 is an immunomodulator that acts as an functional antagonist of sphingosine-1-phosphate (S1P)-mediated signaling. Treatment with any of these molecules selectively induced apoptosis in leukemic LGL.
Figure 3
Figure 3. SERPINB9 IS OVEREXPRESSED IN LEUKEMIC LGL COMPARED TO ACTIVATED NORMAL ENRICHED CD8+ CELLS
Quantitative real-time PCR was performed and analyzed as described.16 Primers used for SERPINB9 are : Forward 5’-AGATGGCCCAGGCACTGTC-3’ and Reverse: 5’- AGAGCCTGTTGGCCGTTCTC-3’. Figure shows that SERPINB9 is overexpressed in T-LGL leukemia PBMC (●, n=9) by more than 30-fold compared to activated enriched normal CD8+ T-cells (○, n=3; P<0.05). Each dot represents expression in an individual PBMC sample, while bar (−) represents mean of observations in a group.
Figure 4
Figure 4. CROSS-TALK AMONG VARIOUS SIGNALING PATHWAYS IN LEUKEMIC LGL
Various survival signaling pathways interact and cross-regulate each other at various levels. It is this dynamic interaction that leads to survival in leukemic LGL. Figure shows known survival signaling pathways and their interactions. Legends used: red - upregulation and/or constitutive activation, green - deregulation, blue – downregulation/or constitutive inhibition; white - no direct information available in LGL leukemia; golden – state of a cell or its component such as apoptosis and mitochondrial integrity loss, rectangle – intracellular component, circle - extracellular component; blue edges – activation/enhancement, red edges – inhibition or downregulation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Loughran T, Kadin M, Starkebaum G, et al. Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. Annals of Internal Medicine. 1985;102(2):169–175. - PubMed
    1. Loughran TP., Jr Clonal diseases of large granular lymphocytes. Blood. 1993;82(1):1–14. - PubMed
    1. Smyth MJ, Kelly JM, Sutton VR, et al. Unlocking the secrets of cytotoxic granule proteins. J Leukoc Biol. 2001;70(1):18–29. - PubMed
    1. Van Lier RAW, Ten Berge IJM, Gamadia LE. Human CD8(+) T-cell differentiation in response to viruses. Nat Rev Immunol. 2003;3(12):931–939. - PubMed
    1. Krammer PH. CD95's deadly mission in the immune system. Nature. 2000;407(6805):789–795. - PubMed

Publication types

Substances

  NODES
Association 1
INTERN 1
twitter 2