Interleukin-15 Enhances Proteasomal Degradation of Bid in Normal Lymphocytes: Implications for Large Granular Lymphocyte Leukemias

Hodge, Deborah L.; Yang, Jun; Buschman, Matthew D.; Schaughency, Paul; Dang, Hong Anh; Bere, William; Yang, Yili; Savan, Ram; Subleski, Jeff; Yin, Xiao Ming; Loughran, Thomas P.; Young, Howard A.

doi:10.1158/0008-5472.can-08-3735

Cited by 60 publications

(57 citation statements)

References 47 publications

(49 reference statements)

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“…Both IL-2 and IL-15 utilize IL-2Rg/b heterodimers to transmit proliferative and survival signals to NK cells and have been shown to induce, enhance or maintain various members of the Bcl-2 family of anti-apoptotic proteins including Bcl-2, Bcl-xL and Mcl-1 (refs [14][15][16][17][18][19][20]. On the flipside, we previously proposed that IL-15 regulates NK cell survival by inhibiting the activation of the BH3-only protein Bim 14 .…”

mentioning

confidence: 99%

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Sathe

Delconte

Souza-Fonseca-Guimarães

et al. 2014

Nat Commun

162

154

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The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3 0 -UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.

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mentioning

confidence: 99%

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Sathe

Delconte

Souza-Fonseca-Guimarães

et al. 2014

Nat Commun

162

154

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“…These data provide a novel molecular mechanism for interleukin-15 control of Bid which potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid. 24 While the hallmark of T-LGL leukemia is the proliferation of fully differentiated clonal CTL which fail to undergo AICD, the mechanism sustaining the proliferation of NK cells in CLPD-NK is less clear. Rather than being the result of a failure of apoptotic pathways, several data suggest that a persistence of antigenic stimulation represents a central mechanism in the pathogenesis of this disease.…”

mentioning

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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“…Interleukina 15, należąca do rodziny IL-2, powoduje ekspresję białek rodziny BCL-1 (BCL-2 i BCL-XL) i, poprzez aktywację szlaków sygnałowych, podtrzymuje populację zarówno prawidłowych komórek pamięci CD8+ i komórek NK, jak i białaczkowych komórek T-LGL [13,34]. Wykazano, że podjednostka rozpuszczalnego receptora IL-15Ra ma regulujący wpływ na komórki jednojądrzaste krwi obwodowej pacjentów z białaczką T-LGL.…”

Section: Etiopatogenezaunclassified

Białaczki z dużych ziarnistych limfocytów T i komórek naturalnej cytotoksyczności

Budziszewska¹

2015

Hematologia

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Streszczenie Białaczki z dużych ziarnistych limfocytów (LGL) obejmują biologicznie heterogenną grupę rzadkich nowotworów układu chłonnego wywodzących się z limfocytów T (T-LGL) lub z komórek naturalnej cytotoksyczności (NK-LGL Abstract Leukemias of large granular lymphocytes (LGL) include a heterogeneous group of rare lymphoid malignancies derived from T cells (T-LGL) and natural killers (NK-LGL) T-LGL leukemia arises from long-term antigen stimulation and the survival of LGL cells is associated with constitutive activation of anti-apoptotic intracellular pathways JAK/STAT, RAS/RAF/MEK/ERK

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Interleukin-15 Enhances Proteasomal Degradation of Bid in Normal Lymphocytes: Implications for Large Granular Lymphocyte Leukemias

Cited by 60 publications

References 47 publications

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

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

Białaczki z dużych ziarnistych limfocytów T i komórek naturalnej cytotoksyczności

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