STAT3 mutation impacts biological and clinical features of T-LGL leukemia

STAT3 mutations have been described in 30-40% of T-large granular lymphocyte (T-LGL) leukemia patients, leading to STAT3 pathway activation. Considering the heterogeneity of the disease and the several immunophenotypes that LGL clone may express, the aim of this work was to evaluate whether STAT3 mutations might be associated with a distinctive LGL immunophenotype and/or might be indicative for specific clinical features.Our series of cases included a pilot cohort of 101 T-LGL leukemia patients (68 CD8+/CD4- and 33 CD4+/CD8\ub1) from Padua Hematology Unit (Italy) and a validation cohort of additional 20 patients from Rennes Hematology Unit (France).Our results indicate that i) CD8+ T-LGL leukemia patients with CD16+/CD56- immunophenotype identify a subset of patients characterized by the presence of STAT3 mutations and neutropenia, ii) CD4+/CD8\ub1 T-LGL leukemia are devoid of STAT3 mutations but characterized by STAT5b mutations, and iii) a correlation exists between STAT3 activation and presence of Fas ligand, this molecule resulting highly expressed in CD8+/CD16+/CD56- patients. Experiments with stimulation and inhibition of STAT3 phosphorylation confirmed this relationship. In conclusion, our data show that T-LGL leukemia with specific molecular and phenotypic patterns is associated with discrete clinical features contributing to get insights into molecular bases accounting for the development of Fas ligand-mediated neutropenia

Legendre-Gauss-Lobatto grids and associated nested dyadic grids

Legendre-Gauss-Lobatto (LGL) grids play a pivotal role in nodal spectral methods for the numerical solution of partial differential equations. They not only provide efficient high-order quadrature rules, but give also rise to norm equivalences that could eventually lead to efficient preconditioning techniques in high-order methods. Unfortunately, a serious obstruction to fully exploiting the potential of such concepts is the fact that LGL grids of different degree are not nested. This affects, on the one hand, the choice and analysis of suitable auxiliary spaces, when applying the auxiliary space method as a principal preconditioning paradigm, and, on the other hand, the efficient solution of the auxiliary problems. As a central remedy, we consider certain nested hierarchies of dyadic grids of locally comparable mesh size, that are in a certain sense properly associated with the LGL grids. Their actual suitability requires a subtle analysis of such grids which, in turn, relies on a number of refined properties of LGL grids. The central objective of this paper is to derive just these properties. This requires first revisiting properties of close relatives to LGL grids which are subsequently used to develop a refined analysis of LGL grids. These results allow us then to derive the relevant properties of the associated dyadic grids.Comment: 35 pages, 7 figures, 2 tables, 2 algorithms; Keywords: Legendre-Gauss-Lobatto grid, dyadic grid, graded grid, nested grid

Lack of common TCRA and TCRB clonotypes in CD8+/ TCRαβ+ T-cell large granular lymphocyte leukemia: A review on the role of antigenic selection in the immunopathogenesis of CD8+ T-LGL

Clonal CD8 +/T-cell receptor (TCR)αβ+ T-cell large granular lymphocyte (T-LGL) proliferations constitute the most common subtype of T-LGL leukemia. Although the etiology of T-LGL leukemia is largely unknown, it has been hypothesized that chronic antigenic stimulation contributes to the pathogenesis of this disorder. In the present study, we explored the association between expanded TCR-Vβ and TCR-V clonotypes in a cohort of 26 CD8 +/TCRαβ + T-LGL leukemia patients, in conjunction with the HLA-ABC genotype, to find indications for common antigenic stimuli. In addition, we applied purpose-built sophisticated computational tools for an in-depth evaluation of clustering of TCRβ (TCRB) complementarity determining region 3 (CDR3) amino-acid LGL clonotypes. We observed a lack of clear TCRA and TCRB CDR3 homology in CD8 +/ TCRαβ + T-LGL, with only low level similarity between small numbers of cases. This is in strong contrast to the homology that is seen in CD4 +/TCRβ + T-LGL and TCRγδ + T-LGL and thus underlines the idea that the LGL types have different etiopathogenesis. The heterogeneity of clonal CD8 +/ TCRαβ + T-LGL proliferations might in fact suggest that multiple pathogens or autoantigens are involved

Emergence of a STAT3 mutated NK clone in LGL leukemia

AbstractLarge granular lymphocyte (LGL) leukemia is a chronic clonal lymphoproliferative disorder. Here, a T-LGL leukemia patient developed NK-LGL leukemia with residual leukemic T-LGL. TCRVβ usage and CDR3 sequence drifts were observed with disease progression. A STAT3 S614R mutation was identified in NK but not T-cells in the mixed leukemic stage. Multiple, non-dominant T-cell clones with distinct STAT3 mutations were present throughout. Our results suggest that T and NK-LGL leukemia may share common pathogenesis mechanisms and that STAT3 mutation alone is insufficient to bring about clonal expansion. Mutational and immunological monitoring may provide diagnostic and therapeutic significance in LGL leukemia

Structurally Conserved Interaction of Lgl Family with SNAREs Is Critical to Their Cellular Function

The Lethal giant larvae (Lgl) tumor suppressor family is conserved from yeast to mammals and plays a critical yet controversial role in cell polarity. Studies on Drosophila Lgl suggest that its function in polarity is through regulation of the acto-myosin cytoskeleton. In contrast, studies on the yeast Lgl homologs, Sro7/Sro77, suggest a function in exocytosis through interaction with the t-SNARE Sec9. Using yeast/mammalian Lgl chimeras, we demonstrate that the overall architecture of Lgl proteins is highly conserved and that the C-terminal domain is the major site of SNARE interaction within both yeast and mammalian homologs. Importantly, we find that the ability of Lgl chimeras to function as the only source of Lgl in yeast correlates precisely with the ability to interact with the yeast t-SNARE. We report a novel interaction between Sro7 and the yeast myosin V, Myo2. However, we find that interactions with either Myo2 or Myo1 (myosin II) cannot account for the dramatic functional differences observed for these chimeras in yeast. These results provide the first demonstration that the interaction of an Lgl family member with a specific effector is critical to its function in vivo. These data support the model that the Lgl family functions in cell polarity, at least in part, by regulating SNARE-mediated membrane delivery events at the cell surface

Aggressive variant large granular lymphocytic leukaemia: a case report

Clonal disorders of LGL may either be CD3+ CD56- or CD3- CD56+ phenotype and these have been designated as T-cell leukaemia (T-LGL) or natural killer cell (NK)-LGL leukaemia respectively. Clonality is usually demonstrated by clonal rearrangement of T-cell receptor gene rearrangement or identified by flowcytometry analysis. Most patients with T-LGL will have an indolent course. In this report we described an aggressiveness of disease in a patient with clonal CD3+ LGL leukaemia whose cells also co-expressed CD56 diagnosed by flowcytometry. The patient responded well to interrupt all standard risk protocol however succumbed to her disease while waiting for upfront stem cell transplant. This case highlights on both the classical laboratory findings of rare entity of disease as well as a review of the literature pertaining particularly on its management

Clonal T-cell large granular lymphocyte proliferations in childhood and young adult immune dysregulation conditions

BackgroundProliferation of large granular lymphocytes (LGL) and T- cell LGL (T- LGL) in peripheral blood along with demonstration of clonality are the hallmarks of a heterogeneous group of disorders, including T- LGL leukemia or T- LGL lymphocytosis. They are often associated with neutropenia and responsive to immunosuppression. The true nature of this entity is not well understood. Some cases are reported as reactive phenomena with very limited experience in pediatric population.MethodsHematology/Oncology Flow Cytometry Laboratory database has been reviewed retrospectively. Patients with identifiable distinct CD5- dim T- cell population and positive clonal T- cell receptor rearrangement were included in the analysis. Clinical and laboratory data were then reviewed.ResultsSixteen cases of children and young adults with increased peripheral blood clonal T- LGL population characterized by dim CD5 expression with wide range of underlying immune dysregulation/stimulation disorders were reviewed. Extended follow up with repeat testing suggested the reactive nature of persistent clonal T- LGL proliferations in this group.ConclusionsOur observations indicate that clonal T- LGL proliferations in children and young adults are reactive in nature and some can be persistent with an indolent course with unknown consequentiality. Clonal T- LGL cells could be targeting the most prominent immunogenic stressor(s) involved as a control mechanism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154679/1/pbc28231.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154679/2/pbc28231_am.pd