Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

Risitano, Antonio M.; Maciejewski, Jaroslaw P.; Muranski, Pawel; Wlodarski, Marcin W.; O’Keefe, Christine L.; Sloand, Elaine M.; Young, Neal S.

doi:10.1038/sj.leu.2403617

Cited by 66 publications

(44 citation statements)

References 36 publications

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“…53 This observation is consistent with observations from human aplastic anemia and paroxysmal nocturnal hemoglobinuria patients in which clonal expansion of CD8 T lymphocytes were detected by Vβ analyses as well as by complementarity-determining-region-3 molecular analysis. 6,55 In immune-mediated BM failure, damage to hematopoiesis may be caused by the excessive action of tumor necrosis factor-alpha and interferon-gamma (IFN-γ) secreted by activated CD8 + T cells. 43 This is consistent with findings from human aplastic anemia patients in which activated cytotoxic T lymphocytes infiltrate aplastic BM and produce detectable amounts of IFN-γ mRNA.…”

Section: Infusion-induced Bm Failurementioning

confidence: 99%

Animal Models for Acquired Bone Marrow Failure Syndromes

Chen¹

2005

Clinical Medicine & Research

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Section: Infusion-induced Bm Failurementioning

confidence: 99%

Animal Models for Acquired Bone Marrow Failure Syndromes

Chen¹

2005

Clinical Medicine & Research

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“…As a consequence of the increased levels of circulating immune complexes in these patients, the frequent positivity of serum neutrophil antibodies is of marginal significance. Overlapping syndromes of LGL disorders, myelodysplasia, and paroxysmal nocturnal hemoglobinuria 33,34 also favor the notion that an immune denominator accounts for this disease.…”

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confidence: 99%

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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“…The association of PNH with clonal T cell populations has been reported recently, using flow cytometric and molecular analyses of the T cell receptor bchain variable region [6][7][8][9][10]. In our case, we detected T cell clones using a PCR-based method to analyze TCR-Vg.…”

Section: Discussionmentioning

confidence: 69%

A patient with paroxysmal nocturnal hemoglobinuria, T cell large granular lymphocyte clonal expansion, and monoclonal gammopathy of undetermined significance

Fukumoto¹,

Gotlib

2006

Am. J. Hematol.

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Paroxysmal nocturnal hemoglobinuria (PNH) has been described in association separately with T cell large granular lymphocyte (LGL) clonal expansions and plasma cell dyscrasias. We describe a patient with anemia related to hemolytic PNH, with concurrent T cell LGL oligoclonal expansion and IgG k monoclonal gammopathy of undetermined significance. Peripheral blood flow cytometry revealed decreased expression of CD55 and CD59 on erythrocytes and decreased expression of CD55 and CD66 on neutrophils. An LGL population was present in the peripheral blood and was characterized as oligoclonal by polymerase chain reaction-based analysis of the T cell receptor c-chain variable region. Serum protein electrophoresis with immunofixation showed a low level IgG k monoclonal protein.We describe the diagnostic evaluation of this patient and provide a brief review of the reported associations among PNH, LGL clonal expansion, and monoclonal gammopathy.

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Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients

Cited by 66 publications

References 36 publications

Animal Models for Acquired Bone Marrow Failure Syndromes

Animal Models for Acquired Bone Marrow Failure Syndromes

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

A patient with paroxysmal nocturnal hemoglobinuria, T cell large granular lymphocyte clonal expansion, and monoclonal gammopathy of undetermined significance

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