The Impact of Epigenetic Modifications in Myeloid Malignancies

Venney, Deirdra; Mohd‐Sarip, Adone; Mills, Ken

doi:10.3390/ijms22095013

Cited by 19 publications

(20 citation statements)

References 99 publications

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“…In contrast, a variety of mutations in epigenetic modifiers ( TET2 , DNMT3A , IDH1/2 ), transcription factors ( TP53 , RUNX1 , IKZF1 ), and splicing factors ( SF3B1 , U2AF1 , SRSF2 ) have been identified and assigned a role in progression from ET or PV to sMF or from MPN-CP to MPN-BP, with an associated myelodysplastic phenotype that increases with the number of these mutations [ 4 ]. This is supported by the fact that these mutations are even more frequently mutated in myelodysplastic syndromes (MDS) and AML [ 37 ]. Some of these mutations modify stem and progenitor cell function and have an intricate role in clonal hematopoiesis of indeterminate potential (CHIP), resulting in skewing towards myeloid differentiation.…”

Section: Etiology Of Mpn Progressionmentioning

confidence: 99%

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Baumeister

Chatain

Sofias

et al. 2021

Cells

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Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.

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Section: Etiology Of Mpn Progressionmentioning

confidence: 99%

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Baumeister

Chatain

Sofias

et al. 2021

Cells

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“…Nowadays, the treatment strategies for AML are chosen based on age and prognostic stratification, which is determined by cytogenetic and molecular alterations (16)(17)(18). Thanks to recent technological advancement in the field of genome research, studying genomic changes and epigenetic modifications in AML cell lines, such as abnormal DNA methylation, has gained more and more interest (19)(20)(21), while using the demethylating agents (HMAs) is definitely effective, especially for patients who are implicated in abnormalities of epigenetic regulation (22,23). However, HMAs yield low r e s p o n s e r a t e s ( 1 0 % -5 0% , i n c l u d i n g h e m a t o l o g i c improvement) and are not curative, with a median OS of less than 1 year.…”

Section: Discussionmentioning

confidence: 99%

Methylation of SPRED1: A New Target in Acute Myeloid Leukemia

Wang

et al. 2022

Front. Oncol.

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Sprouty-related, EVH1 domain-containing protein 1 (SPRED1) has been identified as a novel tumor suppressor gene in acute myeloid leukemia (AML). Previous studies showed that SPRED1 methylation levels were significantly increased in AML patients, making it an interesting candidate for further investigations. To confirm the association of SPRED1 methylation, clinical parameters, and known molecular prognosticators and to identify the impact of methylation level on treatment outcome, we conducted this study in a larger cohort of 75 AML patients. Significantly increased methylation levels of SPRED1 were detected at four of ten CpG units by quantitative high-resolution mass spectrometry-based approach (MassARRAY) in AML patients. Whereas overall survival (OS) and relapse-free survival (RFS) showed no statistical difference between hypermethylation and hypomethylation subgroups, the relationship between methylation level and treatment response was indicated in paired samples from pre- and post-induction. To determine the possible mechanism of SPRED1 methylation in AML, we performed in vitro experiments using THP-1 cells, as the latter showed the highest methylation level (determined by utilizing bisulfite modification) among the three AML cell lines we tested. When treated with 5-AZA and lentivirus transfection, upregulated SPRED1 expression, decreased cell proliferation, increased cell differentiation and apoptosis, and inactivated phosphorylated extracellular signal-regulated kinase (p-ERK) were detected in THP-1 cells. These results show that demethylation of SPRED1 can inhibit the proliferation of AML cells and promote their differentiation and apoptosis, possibly by the ERK pathway. The hypermethylation of SPRED1 is a potential therapeutic target for AML.

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“…Hematological myeloid malignancies are a group of disorders characterized by clonal expansion of hematopoietic stem/progenitor cells, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Epigenetic processes such as DNA methylation and histone modifications with roles in regulating gene(s) expression have been proved to play a vital role in myeloid malignancies [ 3 ]. Recurrent somatic mutations have been identified in genes involved in epigenetic regulators such as TET2 , DNMT3A , IDH1 / 2 and EZH2 that were required for malignant transformation [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation-mediated differential expression of DLX4 isoforms has opposing roles in leukemogenesis

et al. 2022

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Background Previously, we reported the expression of DLX4 isoforms (BP1 and DLX7) in myeloid leukemia, but the functional role of DLX4 isoforms remains poorly understood. In the work described herein, we further determined the underlying role of DLX4 isoforms in chronic myeloid leukemia (CML) leukemogenesis. Methods The expression and methylation of DLX4 isoforms were detected by real-time quantitative PCR (RT-qPCR) and real-time quantitative methylation-specific PCR (RT-qMSP) in patients with CML. The functional role of DLX4 isoforms was determined in vitro and in vivo. The molecular mechanism of DLX4 isoforms in leukemogenesis was identified based on chromatin immunoprecipitation with high-throughput sequencing (ChIP-Seq)/assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) and RNA sequencing (RNA-Seq). Results BP1 expression was increased in patients with CML with unmethylated promoter, but DLX7 expression was decreased with hypermethylated promoter. Functionally, overexpression of BP1 increased the proliferation rate of K562 cells with S/G2 promotion, whereas DLX7 overexpression reduced the proliferation rate of K562 cells with G1 arrest. Moreover, K562 cells with BP1 overexpression increased the tumorigenicity in NCG mice, whereas K562 cells with DLX7 overexpression decreased the tumorigenicity. Mechanistically, a total of 91 genes including 79 messenger RNAs (mRNAs) and 12 long noncoding RNAs (lncRNAs) were discovered by ChIP-Seq and RNA-Seq as direct downstream targets of BP1. Among the downstream genes, knockdown of RREB1 and SGMS1-AS1 partially revived the proliferation caused by BP1 overexpression in K562 cells. Similarly, using ATAC-Seq and RNA-Seq, a total of 282 genes including 151 mRNA and 131 lncRNAs were identified as direct downstream targets of DLX7. Knockdown of downstream genes PTPRB and NEAT1 partially revived the proliferation caused by DLX7 overexpression in K562 cells. Finally, we also identified and validated a SGMS1-AS1/miR-181d-5p/SRPK2 competing endogenous RNA (ceRNA) network caused by BP1 overexpression in K562 cells. Conclusions The current findings reveal that DNA methylation-mediated differential expression of DLX4 isoforms BP1 and DLX7 plays opposite functions in leukemogenesis. BP1 plays an oncogenic role in leukemia development, whereas DLX7 acts as a tumor suppressor gene. These results suggest DLX4 as a therapeutic target for antileukemia therapy.

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The Impact of Epigenetic Modifications in Myeloid Malignancies

Cited by 19 publications

References 99 publications

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Methylation of SPRED1: A New Target in Acute Myeloid Leukemia

DNA methylation-mediated differential expression of DLX4 isoforms has opposing roles in leukemogenesis

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