Network model of survival signaling in large granular lymphocyte leukemia

Zhang, Ranran; Shah, Mithun Vinod; Yang, Jun; Nyland, Susan B.; Liu, Xin; Yun, Jong K.; Albert, Réka; Loughran, Thomas P.

doi:10.1073/pnas.0806447105

Cited by 339 publications

(422 citation statements)

References 41 publications

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“…23 Of great interest is the model suggesting that the persistence of interleukin-15 and platelet-derived growth factor is sufficient to reproduce all known deregulations in leukemic T-LGL. 10 Interleukin-15 alters expression of Bcl-2 family members, i.e. Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1.…”

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confidence: 99%

“…This would lead to the expansion of a fully differentiated effector cytotoxic LGL which is not eliminated as a consequence of an impairment of apoptotic pathways. 10 This is particularly true for T-LGL leukemia. Early data suggesting the pathogenic role of EBV or human T-cell leukemia viruses (HTVL) has been reported in some but not all cases.…”

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confidence: 99%

“…T-LGL leukemia is characterized by an abnormal clonal expansion of antigen-primed mature cytotoxic T-lymphocytes (CTL) which successfully escape AICD and remain competent in the long-term. 10 Clearance of potentially harmful antigen-stimulated effector cytotoxic T-cells after a successful immune response occurs physiologically by triggering Fas-mediated apoptosis through induction of a death-inducing signaling complex (DISC). This process, which is crucial to T-cell homeostasis, requires fine tuning between proliferation, survival, and apoptosis.…”

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confidence: 99%

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Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Zambello¹,

Semenzato²

2009

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nhaplotype with a higher frequency than the normal population, as occurs in patients with rheumatoid arthritis. In recent years progress has been made in understanding the mechanisms sustaining T-LGL leukemia and CLPD-NK. It is now becoming evident that the phenotype of T-cell LGL leukemia is consistent with that of fully differentiated cytotoxic T lymphocytes. The hallmark of T-LGL leukemia lymphocytes is the failure to undergo activation-induced cell death (AICD), this event being consequent to a critical impairment of apoptotic pathways. T-LGL leukemia is characterized by an abnormal clonal expansion of antigen-primed mature cytotoxic T-lymphocytes (CTL) which successfully escape AICD and remain competent in the long-term. 10 Clearance of potentially harmful antigen-stimulated effector cytotoxic T-cells after a successful immune response occurs physiologically by triggering Fas-mediated apoptosis through induction of a death-inducing signaling complex (DISC). This process, which is crucial to T-cell homeostasis, requires fine tuning between proliferation, survival, and apoptosis. Like normal activated CTL, leukemic T-LGL cells exhibit activation of multiple survival signaling pathways. 6 However, unlike normal activated CTL, leukemic T-LGL cells are not sensitive to Fas-induced apoptosis, 20 a process that is essential for AICD. 21 Fas resistance can occur in cells with overexpression of the DISC inhibitory protein c-FLIP. This latter is constitutively expressed in leukemic LGL and prevents DISC formation and Fas-mediated apoptosis. 22 Several genes are likely to be involved in the above mentioned processes and gene expression profiling has revealed that leukemic LGL are characterized by the expression of genes affecting apoptosis, regulation of TCR signaling and immune response. 23 This supports the view that an uncoupling of activation and apoptotic pathways is responsible for the failure of AICD. In fact, genes that are up-regulated in leukemic LGL have antiapoptotic functions whereas those that are down-regulated are pro-apoptotic. Pathway-based microarray analysis also indicated that the balance of pro-apoptotic (ceramide and its analogs) and anti-apoptotic (sphingosine-1-phosphate, S1P) sphingolipid-mediated signaling is deregulated in leukemic LGL in favor of S1P. 23 Of great interest is the model suggesting that the persistence of interleukin-15 and platelet-derived growth factor is sufficient to reproduce all known deregulations in leukemic T-LGL. 10 Interleukin-15 alters expression of Bcl-2 family members, i.e. Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1. Genes belonging to the BCL-2 family, such as the BCL-2 related X gene (BAX) are down-regulated, while the myeloid cell factor (MCL-1) is up-regulated. In primary leukemic LGL, Bid (which is down-regulated by interleukin-15) levels are low but are reversed following bortezomib treatment, with subsequent increases in LGL apoptosis. These data provide a novel molecular mechanism for interleukin-15 control of Bid whi...

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Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Zambello¹,

Semenzato²

2009

Haematologica

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“…To overcome the limitations which is related to representing species as one or zero in [112] approach, Aldridge et al [113] extended it to adjust intermediate activity states using fuzzy logic.…”

Section: Systems Biology Based Methodsmentioning

confidence: 99%

“…Ranran Zhang et al [112] constructed a Boolean logic model of apoptosis signaling in Leukemic T-Cell large granular lymphocytes. They depended on experimental validation to investigate the effect of two defined species that dominate apoptosis, sphingosine kinase 1 and NFκB.…”

Section: Systems Biology Based Methodsmentioning

confidence: 99%

In-Silico Methodologies for Cancer Multidrug Optimization

Hasan¹,

Eldin

Khedr

et al. 2018

IJCT

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Drug combinations is considered as an effective strategy designed to control complex diseases like cancer. Combinations of drugs can effectively decrease side effects and enhance adaptive resistance. Therefore, increasing the likelihood of defeating complex diseases in a synergistic way. This is due to overcoming factors such as off-target activities, network robustness, bypass mechanisms, cross-talk across compensatory escape pathways and the mutational heterogeneity which results in alterations within multiple molecular pathways. The plurality of effective drug combinations used in clinic were found out through experience. The molecular mechanisms underlying these drug combinations are often not clear. It is not easy to suggest new drug combinations. Computational approaches are proposed to reduce the search space for defining the most promising combinations and prioritizing their experimental evaluation. In this paper, we review methods, techniques and hypotheses developed for in silico methodologies for drug combination discovery in cancer and discuss the limitations and challenges of these methods.

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Cellular Interaction Networks

DasGupta¹,

Liang²

2016

Models and Algorithms for Biomolecules and Molecular Networks

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Network model of survival signaling in large granular lymphocyte leukemia

Cited by 339 publications

References 41 publications

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

In-Silico Methodologies for Cancer Multidrug Optimization

Cellular Interaction Networks

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