Impact of the hypomethylating agent 5-azacytidine on dendritic cells function

Frikeche, Jihane; Clavert, Aline; Delaunay, Jacques; Brissot, Éolia; Grégoire, Marc; Gaugler, Béatrice; Mohty, Mohamad

doi:10.1016/j.exphem.2011.08.004

Cited by 52 publications

(46 citation statements)

References 27 publications

(32 reference statements)

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“…In addition, recent evidence suggested that azacitidine can significantly impact some important immune functions via epigenetic modifications, making it an attractive candidate for pharmacologic manipulation of the immune system. 8 In the present study by Goodyear et al, the adjunctive administration of azacitidine after allo-SCT in a series of 27 AML patients was well tolerated despite the drug being started soon after allo-SCT. Of note, increased numbers of circulating Tregs were detected in patients who had received 3 courses of posttransplant azacitidine compared with a control group of patients studied at similar time points after transplantation.…”

mentioning

confidence: 49%

Azacitidine after allo-SCT: the good without the bad?

Mohty¹,

Chevallier²

2012

Blood

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confidence: 49%

Azacitidine after allo-SCT: the good without the bad?

Mohty¹,

Chevallier²

2012

Blood

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“…AZA administration and toxicity AZA was administered for a median of three cycles (range, [1][2][3][4][5][6][7][8][9][10][11][12], at a dose of 75 mg/m 2 per day for 7 days every 4 weeks for the majority of the patients (92%). AZA dose was reduced to 60 mg/m 2 per day (two patients) for 7 days according to the attending physician because of fear of toxicity.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…However, different studies suggested an immunomodulatory effect of the drug. 9 AZA has been shown to increase the expression of tumor Ags by leukemic cells. [10][11][12][13] AZA can also increase regulatory T cells and CD8 þ tumor-specific T-cell responses both in vitro and in the human clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT

Tessoulin

Delaunay

Chevallier

et al. 2014

Bone Marrow Transplant

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Patients with hematopoietic malignancies relapsing after allogeneic hematopoietic SCT (allo-HSCT) have a poor prognosis. We retrospectively analyzed the patients who received azacitidine in our center in the course of treatment of their post-transplant relapse. We identified 31 patients. Relapse occurred at a median of 3.7 (1.7-37.6) months following allo-HSCT. Patients received a median number of three cycles (1-12) of azacitidine (7 days, 75 mg/m 2 daily). Thirty-nine percent of patients had either a monosomal karyotype or a complex karyotype. Eleven patients (35%) received at least one DLI. Eleven patients responded to azacitidine, with four patients achieving a CR (13%). Median time to best response was 92 (35-247) days, with a median duration of 209 (64-751) days. One-year estimated survival rate was 14%. In conclusion, azacitidine may reinduce durable remissions in very few patients with AML or myelodysplastic syndrome. The toxicity related to azacitidine was high, although it may be difficult to distinguish between treatment-related side effects, namely due to cytopenia and toxicity due to the relapse or disease progression itself. Early administration of azacitidine after transplant followed by DLI should be considered as a pre-emptive therapy for potential relapse in patients with minimal residual disease or high-risk myeloid malignancies.

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“…This hypothesis is supported by a recent study in which blasts from AML patients treated with a DNA hypomethylating agent 5-azacytidine generated DCs with improved cytokine profile and immunostimulatory activity. 44 We and others have shown that 5-azacytidine treatment successfully reexpresses methylationsilenced p15Ink4b in blasts isolated from AML patients and myeloid cell lines. 45,46 However, whereas the presented results in murine primary cells and our preliminary results with human AML-derived cell lines (supplemental Figure 4) support a potential clinical application for immunotherapy, a large experimental study with primary blasts isolated from AML patients with and without silenced (methylated) p15INK4b is required to validate this assumption.…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis is supported by a recent study in which blasts from AML patients treated with a DNA hypomethylating agent 5-azacytidine generated DCs with improved cytokine profile and immunostimulatory activity. 44 We and others have shown that 5-azacytidine treatment successfully reexpresses methylationsilenced p15Ink4b in blasts isolated from AML patients and (A) Cell lysates from RAW264.7 cells expressing empty vector (Mig0) or p15Ink4b (MigDDp15) and treated with LPS (1 g/mL) for the indicated periods were analyzed by Western blot with Abs against the indicated phosphorylated IB␣ (Ser-32) or NF-Bp65 (Ser536) and the total IB␣, NFBp65, and PU.1 (Cell Signaling Technology) proteins. The representative results shown are from the same blot that was stripped and reprobed with anti-actin.…”

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confidence: 99%

The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

Fares

Koller

Humeniuk

et al. 2012

Blood

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The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo-generated BMderived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses. (Blood. 2012;119(21):5005-5015) IntroductionIn acute myeloid leukemia (AML), one of the most common epigenetic abnormalities observed in patients is the transcriptional silencing of p15INK4b (Cdkn2b) by DNA hypermethylation. 1,2 Increased DNA methylation of the p15INK4b gene regulatory sequences has been reported in up to 80% of all patients suffering from AML, and in a high proportion of patients with other hematologic disorders, including myelodysplastic syndrome (MDS), and myeloproliferative neoplasms. 3,4 Clinical observations have established a strong correlation between the methylation levels of p15INK4b and poor prognosis in patients. Hypermethylation also provides a biomarker for the subsequent transformation and progression of the disease to a more aggressive phenotype. 3 The tumor-suppressor function of p15Ink4b for myeloid diseases was confirmed experimentally in an animal model with myeloidspecific deletion of the gene. These mice suffer from a mild form of myeloproliferative neoplasm resembling chronic myelomonocytic leukemia and are strongly predisposed to retrovirus-induced AML. 5 p15INK4b is a cyclin-dependent kinase inhibitor (CDKI) that binds and inhibits the activity of 2 cyclin-dependent kinases, CDK4 and CDK6. This inhibition leads to cell-cycle arrest during the early and mid-G 1 phase. 6 In accordance with its cell cycleinhibitory function, the expression levels of p15Ink4b are reported to be increased during the late maturation stages of myeloid progenitors associated with terminal differentiation into macrophages. 7 p15Ink4b has also been shown to play a role during early stages of hematopoiesis independently from its cell cycleinhibitory function. 8 During ea...

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Impact of the hypomethylating agent 5-azacytidine on dendritic cells function

Cited by 52 publications

References 27 publications

Azacitidine after allo-SCT: the good without the bad?

Azacitidine after allo-SCT: the good without the bad?

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT

The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

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