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2.
Oncotarget ; 6(11): 9612-26, 2015 Apr 20.
Article in English | MEDLINE | ID: mdl-25823822

ABSTRACT

The hypomethylating agents (HMAs) are standard therapy for patients with higher-risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023). Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.


Subject(s)
Antimetabolites/pharmacology , Azacitidine/pharmacology , DNA Methylation/drug effects , Myelodysplastic Syndromes/drug therapy , Programmed Cell Death 1 Receptor/genetics , Promoter Regions, Genetic/genetics , T-Lymphocyte Subsets/metabolism , Aged , Aged, 80 and over , Blood Cells/drug effects , Blood Cells/metabolism , Drug Resistance , Female , Gene Expression Regulation/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/genetics , Leukemia, Myelomonocytic, Chronic/metabolism , Lymphocyte Activation , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/physiology , Promoter Regions, Genetic/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , T-Lymphocyte Subsets/drug effects
3.
Br J Haematol ; 170(3): 372-83, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25907546

ABSTRACT

Baseline characteristics, disease-management and outcome of 1000 lower-risk myelodysplastic syndrome (MDS) patients within the European LeukaemiaNet MDS (EUMDS) Registry are described in conjunction with the validation of the revised International Prognostic Scoring System (IPSS-R). The EUMDS registry confirmed established prognostic factors, such as age, gender and World Health Organization 2001 classification. Low quality of life (EQ-5D visual analogue scale score) was significantly associated with reduced survival. A high co-morbidity index predicted poor outcome in univariate analyses. The IPSS-R identified a large group of 247 patients with Low (43%) and Very low (23%) risk score within the IPSS intermediate-1 patients. The IPSS-R also identified 32 High or Very high risk patients within the IPSS intermediate-1 patients. IPSS-R was superior to the IPSS for predicting both disease progression and survival. Seventy percent of patients received MDS-specific treatment or supportive care, including red blood cell transfusions (51%), haematopoietic growth factors (58%) and iron chelation therapy (8%), within 2 years of diagnosis; while 30% of the patients only required active monitoring. The IPSS-R proved its utility as a more refined risk stratification tool for the identification of patients with a very good or poor prognosis and in this lower-risk MDS population.


Subject(s)
Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/therapy , Registries , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Risk Factors
4.
Cancer Cell ; 25(6): 794-808, 2014 Jun 16.
Article in English | MEDLINE | ID: mdl-24835589

ABSTRACT

Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.


Subject(s)
Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Neoplastic Stem Cells/physiology , Animals , Antigens, CD/biosynthesis , Antigens, CD/immunology , Chromosome Deletion , Chromosomes, Human, Pair 5 , Flow Cytometry , Gene Expression Profiling , Genetic Predisposition to Disease , Heterografts , Humans , Mice , Mice, Inbred NOD , Mutation , Myelodysplastic Syndromes/immunology , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/pathology , Prognosis
5.
Br J Haematol ; 150(3): 293-302, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20497178

ABSTRACT

This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/adverse effects , Azacitidine/adverse effects , DNA Methylation , DNA, Neoplasm/metabolism , Drug Administration Schedule , Epidemiologic Methods , Female , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Neutropenia/chemically induced , Polymerase Chain Reaction/methods , Promoter Regions, Genetic , Remission Induction , Thrombocytopenia/chemically induced , Treatment Outcome
6.
Eur J Haematol ; 76(1): 23-32, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16343268

ABSTRACT

The propensity of myelodysplastic syndrome (MDS) to transform into acute myeloid leukemia (AML) suggests the existence of common pathogenic components for these malignancies. Here, four genes implicated in the development of AML were examined for promoter CpG island hypermethylation in cells from 37 patients with different stages of MDS. Aberrant methylation was detected by polymerase chain reaction amplification of bisulfite-treated DNA followed by denaturing gradient gel electrophoresis. The highest rate of methylation was found for p15INK4B (51%), followed by HIC1 (32%), CDH1 (27%), and ER (19%). Concurrent hypermethylation of > or = 3 genes was more frequent in advanced compared with early-stage MDS (P < or = 0.05), and hypermethylation of p15INK4B was associated with leukemic transformation in early MDS (P < or = 0.05). The median overall survival was 17 months for cases showing hypermethylation of > or = 1 genes vs. 67 months for cases without hypermethylation (P = 0.002). Specifically, promoter hypermethylation identified a subgroup of early MDS with a particularly poor prognosis (median overall survival 20 months vs. 102 months; P = 0.004). In multivariate analysis including stage and thrombocyte count, hypermethylation of > or = 1 genes was an independent negative prognostic factor (P < 0.05). These data suggest that hypermethylation of p15INK4B, HIC1, CDH1, and ER contribute to the development and outcome of MDS.


Subject(s)
Cadherins/genetics , Cyclin-Dependent Kinase Inhibitor p15/genetics , DNA Methylation , DNA-Binding Proteins/genetics , Myelodysplastic Syndromes/genetics , Promoter Regions, Genetic/genetics , Receptors, Estrogen/genetics , Transcription Factors/genetics , Adult , Aged , Aged, 80 and over , DNA, Neoplasm/analysis , DNA, Neoplasm/genetics , Disease-Free Survival , Female , Humans , Kruppel-Like Transcription Factors , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Multivariate Analysis , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Polymerase Chain Reaction , Predictive Value of Tests , Prognosis , Risk Factors
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