Up-regulation of ribosomal genes is associated with a poor response to azacitidine in myelodysplasia and related neoplasms

Beličková, Monika; Merkerová, Michaela Dostálová; Votavová, Hana; J, Válka; Veselá, Jitka; Pejsova, Barbora; Hájková, H; Kléma, Jǐŕı; Čermák, Jaroslav; Jonášová, Anna

doi:10.1007/s12185-016-2058-3

Cited by 15 publications

(15 citation statements)

References 39 publications

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“…Wu et al showed RPL23 , a ribosomal gene was overexpressed in MDS CD34+ cells and associated with poor drug response 37 . Belickova et al also showed increased expression of multiple ribosomal genes correlates with poor azacitidine response and disease progression 38 . We further confirmed one of the top hits, RPL5 , showed significantly increased expression in the CD123+ compartment of the primitive compartment of a high-risk MDS patient in comparison to the CD123− compartment and the primitive compartment (Lin−/CD34+/CD38−) of normal bone marrow (Supplementary fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

Stevens

Khan

et al. 2018

Nat Commun

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Myelodysplastic syndrome (MDS) is a chronic hematologic disorder that frequently evolves to more aggressive stages and in some cases leads to acute myeloid leukemia (AML). MDS arises from mutations in hematopoietic stem cells (HSCs). Thus, to define optimal therapies, it is essential to understand molecular events driving HSC pathogenesis. In this study, we report that during evolution of MDS, malignant HSCs activate distinct cellular programs that render such cells susceptible to therapeutic intervention. Specifically, metabolic analyses of the MDS stem cell compartment show a profound activation of protein synthesis machinery and increased oxidative phosphorylation. Pharmacological targeting of protein synthesis and oxidative phosphorylation demonstrated potent and selective eradication of MDS stem cells in primary human patient specimens. Taken together, our findings indicate that MDS stem cells are reliant on specific metabolic events and that such properties can be targeted prior to the onset of clinically significant AML, during antecedent MDS.

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Section: Resultsmentioning

confidence: 99%

Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

Stevens

Khan

et al. 2018

Nat Commun

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“…Another study of 200 CRC patients revealed a reduced OS associated with a higher level of RPS15A protein 24 . RPL28 upregulation was associated with reduced OS after azacytidine treatment in patients with myelodysplasia and related neoplasms 25 . These studies pointed toward potential functions of ribosome-free RPs that might engage an oncogenic role or suppressing tumor cell proliferation, depending on the RPs proteins involved 18 .…”

Section: Discussionmentioning

confidence: 94%

Germline variability and tumor expression level of ribosomal protein gene RPL28 are associated with survival of metastatic colorectal cancer patients

Labriet

Lévesque

Cecchin

et al. 2019

Sci Rep

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this study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer (mCRC) patients treated with the FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) regimen. The rs4806668G > t of the ribosomal protein gene RPL28 was associated with shorter progression-free survival and overall survival by 5 and 9 months (P = 0.002), with hazard ratios of 3.36 (P < 0.001) and 3.07 (P = 0.002), respectively. The rs4806668T allele was associated with an increased RPL28 expression in transverse normal colon tissues (n = 246, P = 0.007). RPL28 expression was higher in colorectal tumors compared to paired normal tissues by up to 124% (P < 0.001) in three independent datasets. Metastatic cases with highest RPL28 tumor expression had a reduced survival in two datasets (n = 88, P = 0.009 and n = 56, P = 0.009). High RPL28 was further associated with changes in immunoglobulin and extracellular matrix pathways. Repression of RPL28 reduced proliferation by 1.4-fold to 5.6-fold (P < 0.05) in colon cancer HCT116 and HT-29 cells. Our findings suggest that the ribosomal RPL28 protein may influence mCRC outcome. Metastatic colorectal cancer (mCRC) presents a 5-year relative survival just above 10% 1. There are many treatment options for these patients including irinotecan-based chemotherapy. Particularly, the FOLFIRI regimen is composed of irinotecan (CPT-11) used in combination with 5-fluorouracil (5-FU) and folinic acid alone or with targeted therapies 2. Both irinotecan and 5-FU are potent on actively replicating cancer cells. SN-38, the active metabolite of irinotecan, is an inhibitor of topoisomerase I (TOP1). It prevents DNA ligation by directly binding the TOP1-DNA complex, leading to replication arrest, double-strand breaks and cell death 3. 5-FU is a pyrimidine analog that exerts its effect by inhibiting the thymidylate synthetase and DNA synthesis. 5-FU can also be incorporated into RNA during synthesis and interferes with protein synthesis 4. The clinical response to FOLFIRI-based regimens is variable with dose-limiting toxicities occurring in a significant proportion of patients 5,6. Several markers in pharmacokinetic pathways have been linked to severe toxicities. For instance, the UGT1A1*28 polymorphism was established as a predictive marker of severe neutropenia, explained by a decreased UGT1A1

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“…Data (NCBI GEO accession number GSE77750) from our previous genome-wide analysis performed using Illumina microarrays (HumanHT-12 v4 Expression, Illumina, San Diego, CA, USA) were used [ 30 ]. For this project, the expression of only five genes in the DLK1–DIO3 region ( DLK1, RTL1 , DIO3, MEG3, and MEG8 ) and of the CTCF was further considered within our patient cohort (the same 12 patients with MDS/AML-MRC) and 10 controls.…”

Section: Methodsmentioning

confidence: 99%

Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Merkerová

Remešová

Krejčík

et al. 2018

Cells

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The DLK1–DIO3 region contains a large miRNA cluster, the overexpression of which has previously been associated with myelodysplastic syndromes (MDS). To reveal whether this overexpression is epigenetically regulated, we performed an integrative analysis of miRNA/mRNA expression and DNA methylation of the regulatory sequences in the region (promoter of the MEG3 gene) in CD34+ bone marrow cells from the patients with higher-risk MDS and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), before and during hypomethylating therapy with azacytidine (AZA). Before treatment, 50% of patients showed significant miRNA/mRNA overexpression in conjunction with a diagnosis of AML-MRC. Importantly, increased level of MEG3 was associated with poor outcome. After AZA treatment, the expression levels were reduced and were closer to those seen in the healthy controls. In half of the patients, we observed significant hypermethylation in a region preceding the MEG3 gene that negatively correlated with expression. Interestingly, this hypermethylation (when found before treatment) was associated with longer progression-free survival after therapy initiation. However, neither expression nor methylation status were associated with future responsiveness to AZA treatment. In conclusion, we correlated expression and methylation changes in the DLK1–DIO3 region, and we propose a complex model for regulation of this region in myelodysplasia.

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Up-regulation of ribosomal genes is associated with a poor response to azacitidine in myelodysplasia and related neoplasms

Cited by 15 publications

References 39 publications

Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

Germline variability and tumor expression level of ribosomal protein gene RPL28 are associated with survival of metastatic colorectal cancer patients

Relationship between Altered miRNA Expression and DNA Methylation of the DLK1-DIO3 Region in Azacitidine-Treated Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

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