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  • 1
    Abstract: The MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)-cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA-129Met allele in patients (n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft-versus-host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA-129Val/Val genotype carriers was improved when treated with anti-thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-gamma release, and faster co-stimulation of CD8(+) T cells. The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA-129Met variants appeared to reduce the severity of aGVHD.
    Type of Publication: Journal article published
    PubMed ID: 26483398
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  • 2
    ISSN: 1569-8041
    Keywords: clonal heterogeneity ; Hodgkin's disease ; NPM/ALK ; single cell PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The translocation t(2;5)(p23;q35) leads to the fusion of the nucleophosmin gene (NPM) on chromosome 5q35 to the recently described receptor kinase ALK 2p23. It is characteristic of a subgroup of CD30+large-cell anaplastic non-Hodgkin's lymphoma (ALCL). Since some cases of Hodgkin's disease (HD) and ALCL share common features, a common pathogenesis has been proposed in a report of the expression of NPM/ALK fusion mRNA in11/13 Hodgkin's lymphomas. Patients and methods: We approached this question by micro manipulatory isolation of single Hodgkin and Reed–Sternberg (H-RS) cells and subsequent RT-PCR amplification of NPM/ALK fusion cDNA from these single cells. Results: Specificity of cell selection was shown by the HD-specific pattern of EBV-gene expression in single H-RS cells. In 4 out of 7 cases, NPM/ALK fusion cDNA was detected in the RNA from whole lymph node tissue. In2 out of 9 cases, NPM/ALK fusion sequences were amplified from single H-RS cells, albeit in a very low frequency (〈5%). Conclusions: These data indicate that NPM/ALK fusion transcripts do not play an early role in the pathogenesis of HD. Whether the rare expression of NPM/ALK is the result of clonal heterogeneity or an indication for clonal evolution and progression toward ALCL can only be answered by the repeated analysis of indicator cases during the course of the disease.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1569-8041
    Keywords: clonal heterogeneity ; Hodgkin's disease ; NPM/ALK ; single cell PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The translocation t(2;5)(p23;q35) leads to the fusion of thenucleophosmin gene (NPM) on chromosome 5q35 to the recently describedreceptor kinase ALK 2p23. It is characteristic of a subgroup of CD30+large-cell anaplastic non-Hodgkin's lymphoma (ALCL). Since some cases ofHodgkin's disease (HD) and ALCL share common features, a common pathogenesishas been proposed in a report of the expression of NPM/ALK fusion mRNA in11/13 Hodgkin's lymphomas. Patients and methods: We approached this question by micromanipulatoryisolation of single Hodgkin and Reed–Sternberg (H-RS) cells andsubsequent RT-PCR amplification of NPM/ALK fusion cDNA from these singlecells. Results: Specificity of cell selection was shown by the HD-specificpattern of EBV-gene expression in single H-RS cells. In 4 out of 7 cases,NPM/ALK fusion cDNA was detected in the RNA from whole lymph node tissue. In2 out of 9 cases, NPM/ALK fusion sequences were amplified from single H-RScells, albeit in a very low frequency (〈5%). Conclusions: These data indicate that NPM/ALK fusion transcripts donot play an early role in the pathogenesis of HD. Whether the rare expressionof NPM/ALK is the result of clonal heterogeneity or an indication for clonalevolution and progression toward ALCL can only be answered by the repeatedanalysis of indicator cases during the course of the disease.
    Type of Medium: Electronic Resource
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