Aberrant hydroxymethylation in promoter CpG regions of genes related to the cell cycle and apoptosis characterizes advanced chronic myeloid leukemia disease, poor imatinib respondents and poor survival

Guru, Sameer Ahmad; Sumi, Mamta P.; Mir, Rashid; Koner, Bidhan Chandra; Saxena, Alpana

doi:10.1186/s12885-022-09481-9

Cited by 6 publications

(5 citation statements)

References 84 publications

(68 reference statements)

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“…In this study, we associated DAPK1 overexpression and hypomethylation with therapeutic failure, and poorer survival in patients with normal karyotype. DAPK1 has also been associated with resistance to imatinib in chronic myeloid leukemia ( Guru et al, 2022 ), autophagia ( Singh et al, 2016 ), alterations in the p53 signaling pathway in chronic lymphocytic leukemia ( Wang et al, 2014 ) and methylated in myelodysplastic syndrome ( Greco et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

MIR4435-2HG as a possible novel predictive biomarker of chemotherapy response and death in pediatric B-cell ALL

Torres-Llanos,

Zabaleta,

Cruz-Rodriguez

et al. 2024

Front. Mol. Biosci.

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Introduction: Although B-cell acute lymphoblastic leukemia (B-cell ALL) survival rates have improved in recent years, Hispanic children continue to have poorer survival rates. There are few tools available to identify at the time of diagnosis whether the patient will respond to induction therapy. Our goal was to identify predictive biomarkers of treatment response, which could also serve as prognostic biomarkers of death, by identifying methylated and differentially expressed genes between patients with positive minimal residual disease (MRD+) and negative minimal residual disease (MRD-).Methods: DNA and RNA were extracted from tumor blasts separated by immunomagnetic columns. Illumina MethlationEPIC and mRNA sequencing assays were performed on 13 bone marrows from Hispanic children with B-cell ALL. Partek Flow was used for transcript mapping and quantification, followed by differential expression analysis using DEseq2. DNA methylation analyses were performed with Partek Genomic Suite and Genome Studio. Gene expression and differential methylation were compared between patients with MRD−/− and MRD+/+ at the end of induction chemotherapy. Overexpressed and hypomethylated genes were selected and validated by RT-qPCR in samples of an independent validation cohort. The predictive ability of the genes was assessed by logistic regression. Survival and Cox regression analyses were performed to determine the association of genes with death.Results:DAPK1, BOC, CNKSR3, MIR4435-2HG, CTHRC1, NPDC1, SLC45A3, ITGA6, and ASCL2 were overexpressed and hypomethylated in MRD+/+ patients. Overexpression was also validated by RT-qPCR. DAPK1, BOC, ASCL2, and CNKSR3 can predict refractoriness, but MIR4435-2HG is the best predictor. Additionally, higher expression of MIR4435-2HG increases the probability of non-response, death, and the risk of death. Finally, MIR4435-2HG overexpression, together with MRD+, are associated with poorer survival, and together with overexpression of DAPK1 and ASCL2, it could improve the risk classification of patients with normal karyotype.Conclusion:MIR4435-2HG is a potential predictive biomarker of treatment response and death in children with B-cell ALL.

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Section: Discussionmentioning

confidence: 99%

MIR4435-2HG as a possible novel predictive biomarker of chemotherapy response and death in pediatric B-cell ALL

Torres-Llanos,

Zabaleta,

Cruz-Rodriguez

et al. 2024

Front. Mol. Biosci.

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“…Therefore, there is no consensus on its prognostic role. DAPK1 has also been associated with resistance to imatinib in chronic myeloid leukemia (43), autophagia (74), alterations in the p53 signaling pathway in chronic lymphocytic leukemia (40) and methylated in myelodysplastic syndrome (38).…”

Section: Discussionmentioning

confidence: 99%

MIR4435-2HG as a Novel Predictive Biomarker of Chemotherapy Response and Death in Pediatric B-cell All

Torres-Llanos,

Zabaleta,

Cruz-Rodriguez

et al. 2023

Preprint

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Background Although B-cell acute lymphoblastic leukemia (B-cell ALL) survival rates have improved in recent years, Hispanic children continue to have poorer survival rates. There are few tools available to identify from the time of diagnosis whether the patient will respond to induction therapy. Our objective was to identify predictive biomarkers of treatment response, which could also serve as prognostic biomarkers of relapse and death, by identifying methylated and differentially expressed genes between patients with positive minimal residual disease (MRD+) and negative minimal residual disease (MRD-). Methods Tumor blasts were separated by immunomagnetic column and subsequently DNA and RNA were extracted. DNA methylation and mRNA sequencing assays were performed on 19 bone marrows from Hispanic children with B-cell ALL. Partek Flow was used for transcript mapping and quantification, followed by differential expression analysis using DEseq2. DNA methylation analyses were performed with Partek Genomic Suite and Genome Studio. Gene expression and differential methylation were compared between patients with MRD- and MRD + at day 15 and at the end of induction chemotherapy. Overexpressed and hypomethylated genes were selected and validated by RT-qPCR in samples of validation cohort. The predictive ability of the genes was assessed by logistic regression. Survival and Cox regression analyses were performed to determine the association of genes with death. The association of genes with relapse was assessed by RT-qPCR in relapsed patient samples and validated using TARGET-PANCER data. Results DAPK1, CNKSR3, MIR4435-HG2, CTHRC1, NPDC1, SLC45A3, ITGA6, and ASCL2 were overexpressed and hypomethylated in MRD + patients. The overexpression of DAPK1, ASCL2, SCL45A3, NPDC1 and ITGA6 can predict non-response at day 15 and refractoriness. Additionally, higher expression of MIR4435-2HG increases the probability of non-response, death, and the risk of death. MIR4435-2HG is also overexpressed in relapse samples. Finally, MIR4435-2HG overexpression, together with MRD+, are associated with poorer survival, and together with overexpression of DAPK1 and ASCL2, it could improve the risk classification of patients with normal karyotype. Conclusions MIR4435-2HG is a potential predictive and prognosis biomarker in children with B-cell ALL.

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“…Additionally, our research group has also revealed the correlation of SOX30 , ID4 and DLX4 hypermethylation with disease progression in CML [ 19 – 21 ]. A recent study demonstrated that promoter hydroxymethylation of tumor suppressor genes DAPK1 , RIZ1 , P16INK4A , RASSF1A and p14ARF ARF was a characteristic feature of CML disease progression and indicated poor imatinib response and poor overall survival of CML patients to imatinib therapy [ 22 ]. On the basis of our previous study [ 12 ], we further investigated SLIT2 promoter methylation in another myeloid malignancy CML.…”

Section: Discussionmentioning

confidence: 99%

SLIT2 promoter hypermethylation predicts disease progression in chronic myeloid leukemia

Wang

Zhang

et al. 2022

Eur J Med Res

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Background Aberrant DNA methylation plays a crucial role in the progression of myeloid neoplasms. Previously, our literature reported that slit guidance ligand 2 (SLIT2) promoter methylation was associated with disease progression and indicated a poor prognosis in patients with myelodysplastic syndrome. Herein, we further investigated the clinical implications and role of SLIT2 promoter methylation in patients with chronic myeloid leukemia (CML). Methods The level of SLIT2 promoter methylation was determined in 104 CML patients, and its clinical significance was analyzed. Moreover, demethylation studies were performed in K562 cells to determine the epigenetic mechanism by which SLIT2 promoter methylation is regulated in CML. Results The level of SLIT2 promoter methylation was similar between CML patients and controls. However, deeper analysis revealed that the SLIT2 promoter methylation level in the accelerated phase (AP) and blast crisis (BC) was markedly higher than that in the chronic phase (CP) and controls. Additionally, a marked difference was identified between the SLIT2 promoter hypermethylated and non-hypermethylated groups among CML patients grouped by clinical stage. The frequency of SLIT2 hypermethylation was markedly increased with the progression of clinical stage, that is, it was the lowest in CP samples (12/80, 15%), higher in AP samples (4/8, 50%) and the highest in BC samples (11/16, 69%). Importantly, the level/density of SLIT2 promoter methylation was significantly higher in the advanced stage than in the early stage among the 6 tested paired CML patients. Epigenetically, the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 expression was decreased in patients with CML. SLIT2 promoter hypermethylated cases had a markedly lower SLIT2-IT1 expression level than SLIT2 promoter non-hypermethylated cases. Moreover, SLIT2-IT1 and miR-218 expression was remarkably upregulated in a dose-dependent manner after demethylation treatment of K562 cells. Conclusions Hypermethylation of the SLIT2 promoter is correlated with disease progression in CML. Furthermore, SLIT2 promoter methylation may function by regulating the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 during CML progression.

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Aberrant hydroxymethylation in promoter CpG regions of genes related to the cell cycle and apoptosis characterizes advanced chronic myeloid leukemia disease, poor imatinib respondents and poor survival

Cited by 6 publications

References 84 publications

MIR4435-2HG as a possible novel predictive biomarker of chemotherapy response and death in pediatric B-cell ALL

MIR4435-2HG as a possible novel predictive biomarker of chemotherapy response and death in pediatric B-cell ALL

MIR4435-2HG as a Novel Predictive Biomarker of Chemotherapy Response and Death in Pediatric B-cell All

SLIT2 promoter hypermethylation predicts disease progression in chronic myeloid leukemia

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