Functional expression of TRAIL and TRAIL‐R2 during human megakaryocytic development

Melloni, Elisabetta; Secchiero, Paola; Celeghini, Claudio; Campioni, Diana; Grill, Vittorio; Guidotti, Lia; Zauli, Giorgio

doi:10.1002/jcp.20358

Cited by 27 publications

(22 citation statements)

References 34 publications

(52 reference statements)

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“…[38][39][40] Previous studies [41][42][43] show that TRAIL can promote the (A) Cultured with control IgG, megakaryocytes expressed cyclin B1 with a reduction from 44.3% at day 5 to 21.6% at day 9 and a limited expression of cyclin D3 (3.5%) at day 9. Although cultured with patient IgG (from groups A and B), megakaryocytes expressed cyclin B1 at a persistently low level (20.5%) and almost did not express cyclin D3 during the whole culture time.…”

Section: Discussionmentioning

confidence: 99%

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

Yang

Wang

Zhao

et al. 2010

Blood

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Recent in vitro studies provide evidence for autoantibody-induced suppression of megakaryocytopoiesis and show a reduction in megakaryocyte production and maturation in the presence of immune thrombocytopenia (ITP) plasma. Here, we present CD34 ؉ cells from healthy umbilical cord blood mononuclear cells cultured in medium containing thrombopoietin, stem cell factor, interleukin-3, and 10% plasma from either ITP patients or healthy subjects. The quantity, quality, and apoptosis of megakaryocytes were measured. We observed that most ITP plasma boosted megakaryocyte quantity but impaired quality, resulting in significantly less polyploidy cells (N > 4) and platelet release. In these megakaryocytes, we found a lower percentage of cell apoptosis, a lower expression of tumor necrosis factor-related apoptosisinducing ligand (TRAIL), and a higher expression of Bcl-xL.

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Section: Discussionmentioning

confidence: 99%

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

Yang

Wang

Zhao

et al. 2010

Blood

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“…In fact, TRAIL has been recently described as a promoter/inhibitor of the maturation of erythrocytes, megakaryocytes, and monocytes. [17][18][19][20][21] It is well established that several isoforms of PKC have a role in the regulation of TRAIL activity. 19,[21][22][23] In general, PKC isoenzymes play central roles in various cellular signaling pathways, participating in a variety of protein phosphorylation cascades that regulate/modulate cellular structure and gene expression.…”

Section: Introductionmentioning

confidence: 99%

Phorbol ester–induced PKCϵ down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation

Gobbi¹,

Mirandola²,

Carubbi³

et al. 2009

Blood

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Despite the relevant therapeutic progresses made in these last 2 decades, the prognosis of acute myeloid leukemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in turn, is a death ligand that spares normal cells and is therefore currently under clinical trials for cancer therapy. Emerging evidence, however, suggests that TRAIL is also involved in nonapoptotic functions, like cell differentiation. PKC⑀ is differentially modulated along normal hematopoiesis, and its levels modulate the response of hematopoietic precursors to TRAIL. Here, we investigated the effects of the combination of phorbol esters (phorbol ester 4-␤-phorbol-12,13-dibutyrate [PDBu]) and TRAIL in the survival/differentiation of AML cells. We demonstrate here that PDBu sensitizes primary AML cells to both the apoptogenic and the differentiative effects of TRAIL via PKC⑀ down-modulation, without affecting TRAIL receptor surface expression. We believe that the use of TRAIL in combination with phorbol esters (or possibly more specific PKC⑀ down-modulators) might represent a significative improvement of our therapeutic arsenal against AML. (Blood. 2009;113:3080-3087) IntroductionAlthough these last 2 decades have seen relevant progresses in the therapy of acute myelogenous leukemia (AML) in terms of cytogenetic prognostic factors, bone marrow transplantation, and targeted therapies, 1 the 5-year survival rate is still 20% to 30% 2 for adult primary AML, and is even worse for AML arising from myeloproliferative disorders or myelodysplastic syndromes (MDSs). 3 Moreover, conventional antitumor treatments make a selective pressure for p53-inactivated tumor cells, and the development of drug resistance remains a serious problem. In this context, a special effort is currently dedicated to targeted therapies whose cornerstones-at least in terms of clinical success-have been all-trans retinoic acid (ATRA) for promyelocytic leukemia 4,5 and imatinib for chronic myelogenous leukemia, 6 while several other compounds-including apoptosis inducers and antiapoptotic inhibitors-are in the pipeline in the future perspective of combinations of multiple targeted therapies for the treatment of AML.Recombinant, soluble tumor necrosis factor-related apoptosisinducing ligand (TRAIL) is currently being developed as a promising natural immune molecule for patients with cancer because it selectively induces apoptosis in transformed or stressed cells but not in most normal cells. 7 Although primary AML cells are generally resistant to TRAIL-induced apoptosis in patients with cancer, phase 1 and 2 clinical trials using agonistic mAbs that engage the human TRAIL receptors 1 (TRAIL-R1) and 2 (TRAIL-R2) have also provided encouraging results. 7 Although hepatotoxicity was observed as side effect using agonistic antibodies against TRAIL-R2, 8 the emerging idea is that TRAIL will likely be used as one component of more complex antit...

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“…These data established the notion that activation of the extrinsic pathway promotes platelet shedding. Studies of the TNF-related apoptosis-inducing ligand (TRAIL), another death receptor ligand, have provided support for this model, suggesting that TRAIL can promote megakaryocyte maturation 31 , and that reductions in megakaryocyte apoptosis caused by decreased TRAIL expression might contribute to impaired thrombopoiesis in immune thrombocytopenia patients 32 .…”

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confidence: 99%

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

et al. 2014

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Functional expression of TRAIL and TRAIL‐R2 during human megakaryocytic development

Cited by 27 publications

References 34 publications

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

Phorbol ester–induced PKCϵ down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

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