Primary Pulmonary Hypertension in a Patient With CD8/T-cell Large Granulocyte Leukemia*

Rossoff, Leonard J.; Genovese, Joseph; Coleman, Morton; Dantzker, David R.

doi:10.1378/chest.112.2.551

Cited by 42 publications

(35 citation statements)

References 20 publications

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“…Neither had any other cause of pulmonary hypertension and the elevated pulmonary artery pressure improved with treatment of the LGL leukemia. These findings and previous descriptions in the literature 16,17 lead us to consider that the pulmonary artery hypertension resulted from the LGL proliferation.…”

Section: B Bareau Et Alsupporting

confidence: 74%

Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases

Bareau¹,

Rey²,

Hamidou³

et al. 2010

Haematologica

176

206

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BackgroundLarge granular lymphocyte leukemia is a rare lymphoproliferative disorder associated with autoimmune diseases and impaired hematopoiesis. This study describes the clinical and biological characteristics of 229 patients with T-cell or NK-cell large granular lymphocyte leukemia. Design and MethodsThe diagnosis was based on a large granular lymphocyte expansion (> 0.5¥10 9 /L) lasting more than 6 months. Monoclonal T-cell receptor γ gene rearrangement was detected in all the cases of T-cell large granular lymphocyte leukemia. Patients with chronic NK-cell lymphocytosis had an indolent disease, while those with multiorgan large granular lymphocyte infiltration and an aggressive clinical disease were considered to have NK-cell large granular lymphocyte leukemia. ResultsThe diagnosis of T-cell large granular lymphocyte leukemia was confirmed in 201 cases, chronic NK-cell lymphocytosis in 27 cases and NK-cell large granular lymphocyte leukemia in one case. Associated auto-immune diseases or other neoplasms were present in 74 and 32 cases, respectively. One hundred patients (44%) required treatment, mainly for neutropenia-associated infections (n=45), symptomatic auto-immune diseases (n =24), transfusion-dependant anemia (n=18), and other causes (n=13). Patients were treated with steroids (n= 33), methotrexate (n=62), cytoxan (n=32), or cyclosporine (n=24) either as first-, second-, third-or fourth-line therapy. The overall response rate at 3 months and complete response rate for the various treatments were as follows: steroids (12% and 3%), methotrexate (55% and 21%), cytoxan (66% and 47%), cyclosporine (21% and 4%), respectively. Four out of 13 patients responded to splenectomy. Eleven out of 15 patients responded to cytoxan after methotrexate treatment had failed. The mean number of treatments was 3.4 (range, 1-7). There were 15 large granular lymphocyte leukemia-related deaths. ConclusionsPatients with T-cell large granular lymphocyte leukemia and chronic NK-cell lymphocytosis have similar clinical and biological features and responses to treatment. First-line therapy with cytoxan should be tested in a prospective trial.Key words: large granular lymphocyte leukemia, LGL leukemia, NK lymphocytosis.Citation: Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, Schleinitz N, Tournilhac O, Roussel M, Fest T, and

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Section: B Bareau Et Alsupporting

confidence: 74%

Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases

Bareau¹,

Rey²,

Hamidou³

et al. 2010

Haematologica

176

206

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“…Patients who fail first-line therapy may benefit from second-line monotherapy with nucleoside analogues, including fludarabine, 2ʹ-deoxycoformycine, and 2-chloroxyadenosine, or targeted therapy with anti-CD52 antibodies (alemtuzumab, Campath ® ; Berlex Inc., Wayne, NJ) [63][64][65][66].…”

Section: Therapeutic Principlesmentioning

confidence: 99%

Large Granular Lymphocyte Leukemia

2006

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“…1,6,7 T LGLL represents roughly 85% of all reported LGLL cases and the clinical course in these patients is generally characterized by recurrent bacterial infections, anemia, neutropenia, rheumatoid arthritis, and occasionally by pulmonary artery hypertension (PAH). 2,5,6,8,9 Although aberrant immune tolerance as a result of the malignant cytotoxic CD8 ϩ T cells has been suggested, the molecular mechanisms underlying this pathobiology have not been elucidated. 10 Recent studies in LGLL showed that the infiltrating leukemic cells have an association with direct tissue destruction.…”

Section: Large Granular Lymphocytic Leukemia (Lgll) Is a Clonal Disormentioning

confidence: 99%

“…10 Recent studies in LGLL showed that the infiltrating leukemic cells have an association with direct tissue destruction. 5,8,11,12 Moreover, activated CD8 ϩ CD28 null and CD4 ϩ CD28 null T lymphocytes are commonly overexpressed in autoimmune diseases. 9,[13][14][15][16] By microarray analysis, CD4 ϩ CD28 null T cells overexpressed perforin and several natural killer receptors (NKRs).…”

Section: Large Granular Lymphocytic Leukemia (Lgll) Is a Clonal Disormentioning

confidence: 99%

A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia

Chen

Bai

Sokol

et al. 2009

Blood

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IntroductionLarge granular lymphocytic leukemia (LGLL) is a clonal disorder marked by increased numbers of circulating LGLs that have the ability to invade bone marrow, spleen, liver, and lung. 1 LGL proliferations are clonally derived from either CD3 Ϫ /CD56 ϩ or CD3/CD8 ϩ LGLs 2-5 and are designated natural killer LGLL (NK-LGLL) and T-cell LGLL (T LGLL), respectively. 1,6,7 T LGLL represents roughly 85% of all reported LGLL cases and the clinical course in these patients is generally characterized by recurrent bacterial infections, anemia, neutropenia, rheumatoid arthritis, and occasionally by pulmonary artery hypertension (PAH). 2,5,6,8,9 Although aberrant immune tolerance as a result of the malignant cytotoxic CD8 ϩ T cells has been suggested, the molecular mechanisms underlying this pathobiology have not been elucidated. 10 Recent studies in LGLL showed that the infiltrating leukemic cells have an association with direct tissue destruction. 5,8,11,12 Moreover, activated CD8 ϩ CD28 null and CD4 ϩ CD28 null T lymphocytes are commonly overexpressed in autoimmune diseases. 9,[13][14][15][16] By microarray analysis, CD4 ϩ CD28 null T cells overexpressed perforin and several natural killer receptors (NKRs). Acquisition of non-MHC-restricted direct cytotoxicity against known NK tumor targets, normal tissue epithelial cells, and normal endothelial cells after activation in vitro suggested that these NKRs were functional. 17 Activating NKRs typically recognize and bind specific molecules on target cells in the absence of MHC class I or II antigen presentation. 18 Activating NKRs such as those of the killer immunoglobulin-like receptor (KIR), NK cytotoxicity receptor (NCR), and CD94-NKG2 families as well as NKG2D mediate NK-cell direct cytotoxicity and may also impart cytotoxic function to these effector T cells.The binding of activating NKR ligands stimulates a cytoplasmic signaling cascade leading to NK-and T-cell activation and cytotoxicity. 19 Activating NKRs typically partner with and signal via membrane-bound adapter proteins that possess canonical cytoplasmic activation motifs. DAP10 and DAP12 are the adapters that partner with most activating NKRs expressed in NK cells and all NKRs expressed in T cells. DAP12 possesses a cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM; D/ExxYxxL/Ix 6-12 YxxL/I) 20 and signals by activating Syk protein tyrosine kinase, phosphoinositide 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK/MAPK). This signaling pathway results in granule mobilization, target cell lysis, and cytokine production. 19 DAP10 partners exclusively with NKG2D through interaction with a cytoplasmic PI3K binding motif (YxxM), which recruits PI3K after NKG2D recognizes its specific ligands (eg, MICA/MICB) leading to the phosphorylation of AKT and subsequent target cell lysis and cytokine release. 21 Evidence is provided in this study that LGLL cells are CD8 ϩ CD28 null T cells that constitutively express elevated levels of multiple NKRs as well as Submitted July 10, 2008; accept...

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Primary Pulmonary Hypertension in a Patient With CD8/T-cell Large Granulocyte Leukemia*

Cited by 42 publications

References 20 publications

Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases

Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases

Large Granular Lymphocyte Leukemia

A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia

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