The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells

Almstedt, Maika; Blagitko-Dorfs, Nadja; Duque‐Afonso, Jesús; Karbach, Julia; Pfeifer, Dietmar; Jäger, Elke; Lübbert, Michael

doi:10.1016/j.leukres.2010.02.004

Cited by 159 publications

(119 citation statements)

References 43 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…In contrast, we have previously found expression of PRAME to be associated with a reduced overall survival in patients with CML [40] as described for various solid tumors [45][46][47]. In our current study, we did not observe an influence on overall survival despite the association of positivity for PRAME with favorable cytogenetics.…”

Section: Discussioncontrasting

confidence: 86%

“…It has repeatedly been hypothesized that CTA, as targets for tumor-specific immunity, may represent intriguing targets for demethylating therapy, as they are silenced in many hematological cancers and are reactivated by epigenetic therapy [44]. This can in turn lead to an improved tumor recognition [45], and even the expansion of CTA-specific T cells in patients [46]. Others have recently demonstrated that treatment with Decitabine increases expression of CT gene NY-ESO-1 and different MAGE-A genes in AML cell lines and we have shown here that expression of CTA in AML cell lines is indeed strongly regulated by methylation but not by histone deacetylation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

et al. 2011

View full text Add to dashboard Cite

Cancer-testis antigens (CTA) represent attractive targets for tumor immunotherapy. However, a broad picture of CTA expression in acute myeloid leukemia (AML) is missing. CTA expression was analyzed in normal bone marrow (BM) as well as in AML cell lines before and after treatment with demethylating agents and/or histone acetylase inhibitors. Presence of selected CTA with a strictly tumor-restricted expression was then determined in samples of patients with AML before and after demethylating therapy. Screening AML cell lines for the expression of 20 CTA, we identified six genes (MAGE-A3, PRAME, ROPN1, SCP-1, SLLP1, and SPO11) with an AML-restricted expression. Analyzing the expression of these CTA in blast-containing samples from AML patients (N 5 64), we found all samples to be negative for MAGE-A3 and SPO11 while a minority of patients expressed ROPN1 (1.6%), SCP-1 (3.1%), or SLLP1 (9.4%). The only CTA expressed in substantial proportion of patients (53.1%) was PRAME. Following demethylating treatment with 5 0 -aza-2 0 -deoxycytidine, we observed an increased or de novo expression of CTA, in particular of SSX-2, in AML cell lines. In AML patients, we detected increased expression of PRAME and induction of SSX-2 after demethylating therapy with 5-azacytidine. With the exception of PRAME, CTA are mostly absent from AML blasts. However, demethylating treatment induces strong expression of CTA, particularly of SSX-2, in vitro and in vivo. Therefore, we propose that CTA-specific immunotherapy for AML should preferentially target PRAME and/or should be combined with the application of demethylating agents opening the perspective for alternative targets like CTA SSX-2. Am. J. Hematol. 86:918-922, 2011. V

show abstract

Section: Discussioncontrasting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

et al. 2011

View full text Add to dashboard Cite

show abstract

“…In these analyses, HMA have shown to upregulate several antigens on leukemic cells in vitro and in vivo that were previously epigenetically silenced. This includes HLA epitopes, cancer testis antigens and minor histocompatibility molecules thought to render malignant cells more immunogenic toward T cell killing [48][49][50][51]. In further support of this, HMA seem to enhance T-cell mediated antitumor activity by increasing tumor-specific CD8 T cell responses against these upregulated molecules such as cancer testis antigens [52].…”

Section: Mode Of Actionmentioning

confidence: 81%

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

et al. 2017

View full text Add to dashboard Cite

Despite the curative potential of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), many patients will relapse. Until recently therapeutic options mainly consisted of palliative care, chemotherapy, donor lymphocyte infusions and second transplantation in selected cases. Still many patients either do not tolerate intensive therapies or do not achieve durable remissions and will finally succumb. Given this unmet medical need the hypomethylating agents (HMA), Azacitidine (Aza) and Decitabine (DAC) have been tested as salvage therapy in patients with myeloid malignancies relapsing after allo-SCT. Furthermore, they have also been incorporated into prophylactic and pre-emptive approaches to avoid haematological relapse. In this review, we summarize the evidence from retrospective studies but also from a few prospective trials regarding the use of HMA after transplant. To aid clinicians in their daily clinical practice, we also comment on some practical aspects such as dosing and schedule, the choice of HMA and the use of complementary cellular therapies. Finally, this review also gives an overview on potential mechanisms mediating the efficacy of HMA after transplant as well as ongoing preclinical research and clinical activities aiming to further improve this treatment approach.

show abstract

“…Possibly, 5-azacytidine acted as a 'priming' agent and sensitizer to the immune cells, for instance by upregulating cancer/testis antigens in vivo. 20,21 This robust clinical result (very notable particularly in the patients attaining prolonged complete remission, all of whom had received previous DLI only, without attaining CR) add to the clinical settings where azanucleoside treatment can prime leukemia cells or solid tumors to the activity of the subsequent therapy.…”

Section: Discussionmentioning

confidence: 91%

“…Translational studies on primary blasts before and after hypomethylating treatment are warranted to address whether derepression of genes silenced by hypermethylation is causal in boosting immune responses in vivo. 21,25 …”

Section: Discussionmentioning

confidence: 99%

5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft

Steinmann

Bertz

Wäsch

et al. 2015

Bone Marrow Transplant

View full text Add to dashboard Cite

DNA-hypomethylating agents are a viable treatment option for AML/myelodysplastic syndrome (MDS) relapse after allograft by upregulating Ags on blasts before DLI. Seventy-two patients with relapsed AML (n = 62), MDS (n = 8) and other myeloid neoplasms (n = 2) after allograft were treated with low-dose 5-azacytidine and, if feasible, DLI. Patient characteristics: median age 62 years (range 20-75), 42% with adverse cytogenetics, 82% not in remission at transplant and 83% received fludarabine-based reducedtoxicity conditioning. Median duration from transplant to 5-azacytidine was 289 days (range 59-2133). Response criteria: CR, temporary disease control or treatment failure. A median of 2.7 courses (range 1-10) were administered; 65 out of 72 patients also received DLI (41 already before 5-azacytidine). Ten patients developed acute GVHD and two succumbed to treatment-related sepsis. CR rate was 9.7% (in two patients lasting 45 years), 44% had temporary disease control (median duration 71 days, range 31-380). Median survival from 5-azacytidine was 108 days, 21 patients proceeded to subsequent transplant. In multivariate analysis, peripheral blood blasts o 1% were predictive of longer OS (P = 0.03). Taken together, long-term remissions can be induced by this well-tolerated outpatient treatment, particularly in patients without peripheral blood blasts.

show abstract

The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells

Cited by 159 publications

References 43 publications

Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft

Contact Info

Product

Resources

About