The pathogenesis and treatment of large granular lymphocyte leukemia

Steinway, Steven N.; LeBlanc, Francis; Loughran, Thomas P.

doi:10.1016/j.blre.2014.02.001

Cited by 67 publications

(60 citation statements)

References 88 publications

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“…2 The usual treatments include methotrexate, cyclophosphamide (Cytoxan), or cyclosporine A (CsA); these are not curative and can have harsh side effects such as tissue injury, including renal and hepatic, or even induction of other cancers. 3 One dysregulated pathway in LGLL is the Janus kinase (JAK) -signal transducer and activator of transcription (STAT) pathway. JAKs phosphorylate STAT monomers at a conserved tyrosine residue, which allows STAT dimerization and transcription of target genes.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia

Olson

Kulling²,

Olson

et al. 2016

Cancer Biology & Therapy

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Large granular lymphocyte leukemia (LGLL) is a rare incurable chronic disease typically characterized by clonal expansion of CD3C cytotoxic T-cells. Two signal transducer and activator of transcription factors, STAT1 and STAT3, are constitutively active in T-LGLL. Disruption of this activation induces apoptosis in T-LGLL cells. Therefore, considerable efforts are focused on developing treatments that inhibit STAT activation. Calcitriol, the active form of vitamin D, has been shown to decrease STAT1 and STAT3 phosphorylation in cancer cell lines and autoimmune disease mouse models. Thus, we investigated whether calcitriol could be a valid therapeutic for T-LGLL. Calcitriol treatment of the TL-1 cell line (model of T-LGLL) led to decreased phospho-Y701 STAT1 and phospho-Y705 STAT3 and increased vitamin D receptor (VDR) levels. Doses of 10 and 100 nM calcitriol also significantly decreased the inflammatory cytokine IFN-g in the TL-1 cell line. The overall cell viability did not change when the TL-1 cell line was treated with 0.1 to 1000 nM calcitriol. Studies with primary T-LGLL patient peripheral blood mononuclear cells showed that the majority of T-LGLL patients have detectable VDR and activated STATs in contrast to normal donor controls. Treatment of primary T-LGLL patient cells with calcitriol recapitulated findings from the TL-1 cell line. Overall, our results suggest that calcitriol may reprogram T-cells to decrease essential STAT activation and pro-inflammatory cytokine output. These data support further investigation into calcitriol as an experimental therapeutic for T-LGLL.

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Section: Introductionmentioning

confidence: 99%

Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia

Olson

Kulling²,

Olson

et al. 2016

Cancer Biology & Therapy

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“…In the LGLL, activation of survival pathways and evasion of apoptosis are described. These include dysregulated Fas/Fas Ligand, Platelet derived growth factor and IL15, Map kinase, PI3K-Akt, NFB and Jak/STAT [13]. In addition to this dysregulation of apoptosis, a chronic antigen exposure [11] leading to a clonal expansion of LGL may be involved.…”

Section: Discussionmentioning

confidence: 95%

Treatment of pseudo Felty's syndrome: Is there a place for rituximab?

et al. 2015

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“…Dans la leucémie à LGL, l'activation des voies de survie et l'évasion de l'apoptose sont décrites. Celles-ci incluent un dérèglement du ligand Fas/Fas, du facteur de croissance dérivé des plaquettes, l'IL15, Map Kinase, Pi3k-Akt, Nf-b et Jak/STAT [13]. En plus de ce dérèglement de l'apoptose, une exposition chronique aux antigènes [11] entraînant une expansion clonale des LGL peut être incriminée.…”

Section: Discussionunclassified