Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies

Trivedi, Gaurang; Inoue, Daichi; Zhang, Lingbo

doi:10.1016/j.molmed.2021.06.013

Cited by 3 publications

(3 citation statements)

References 94 publications

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“…MDS is a severe hematological disorder that affects ~87,000 individuals worldwide each year. Unfortunately, in approximately one-third of patients, MDS eventually progresses to AML, which is associated with a poor prognosis ( 34 ). Previous research has indicated that MEK inhibitor can reverse resistance to bortezomib in patients with MDS, while PI3K inhibitor can enhance the apoptotic rates of SKM-1 cells ( 35 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases

Zheng,

Chen,

Zhang

et al. 2023

Int J Oncol

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The transformation of myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) poses a significant clinical challenge. The trimethylation of H3 on lysine 27 (H3K27me3) methylase and de-methylase pathway is involved in the regulation of MDS progression. The present study investigated the functional mechanisms of the MEK/ERK and PI3K/AKT pathways in the MDS-to-AML transformation. MDS-AML mouse and SKM-1 cell models were first established and this was followed by treatment with the MEK/ERK pathway inhibitor, U0126, the PI3K/AKT pathway inhibitor, Ly294002, or their combination. H3K27me3 methylase, enhancer of zeste homolog (EZH)1, EZH2, demethylase Jumonji domain-containing protein-3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) and H3K27me3 protein levels were determined using western blot analysis. Cell viability, cycle distribution and proliferation were assessed using CCK-8, flow cytometry, EdU and colony formation assays. The ERK and AKT phosphorylation levels in clinical samples and established models were determined, and SKM-1 cell behaviors were assessed. The levels of H3K27me3 methylases and de-methylases and distal-less homeobox 5 (DLX5) were measured. The results revealed that the ERK and AKT phosphorylation levels were elevated in patients with MDS and MDS-AML, and in mouse models. Treatment with U0126, a MEK/ERK pathway inhibitor, and Ly294002, a PI3K/AKT pathway inhibitor, effectively suppressed ERK and AKT phosphorylation in mice with MDS-AML. It was observed that mice with MDS treated with U0126/Ly294002 exhibited reduced transformation to AML, delayed disease transformation and increased survival rates. Treatment of the SKM-1 cells with U0126/Ly294002 led to a decrease in cell viability and proliferation, and to an increase in cell cycle arrest by suppressing ERK/PI3K phosphorylation. Moreover, treatment with U0126/Ly294002 downregulated EZH2/EZH1 expression, and upregulated JMJD3/UTX expression. The effects of U0126/Ly294002 were nullified when EZH2/EZH1 was overexpressed or when JMJD3/UTX was inhibited in the SKM-1 cells. Treatment with U0126/Ly294002 also resulted in a decreased H3K27me3 protein level and H3K27me3 level in the DLX5 promoter region, leading to an increased DLX5 expression. Overall, the findings of the present study suggest that U0126/Ly294002 participates in MDS-AML transformation by modulating the levels of H3K27me3 methylases and de-methylases, and regulating DLX5 transcription and expression.

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Section: Discussionmentioning

confidence: 99%

MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases

Zheng,

Chen,

Zhang

et al. 2023

Int J Oncol

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“…Myelodysplastic syndrome (MDS) is a heterogeneous disorder characterized by hypoplasia, disturbed differentiation of hematopoietic cells, and increased apoptosis of diseased cells leading to a decrease in one or more lineages, and patients with high-risk MDS (HR-MDS) are predisposed to progression to AML ( Trivedi et al, 2021 ). Decitabine (DAC) is one of the main drugs used in the treatment of HR-MDS, and DAC alone may be resistant by a mechanism that induces NF-E2-related factor 2 (Nrf2) activation and a downstream antioxidant response that inhibits reactive oxygen species (ROS) generation, leading to drug resistance.…”

Section: Malignant Hematologic Diseasesmentioning

confidence: 99%

All-trans retinoic acid in hematologic disorders: not just acute promyelocytic leukemia

Chen,

Tong,

et al. 2024

Front. Pharmacol.

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All-trans retinoic acid (ATRA) plays a role in tissue development, neural function, reproduction, vision, cell growth and differentiation, tumor immunity, and apoptosis. ATRA can act by inducing autophagic signaling, angiogenesis, cell differentiation, apoptosis, and immune function. In the blood system ATRA was first used with great success in acute promyelocytic leukemia (APL), where ATRA differentiated leukemia cells into mature granulocytes. ATRA can play a role not only in APL, but may also play a role in other hematologic diseases such as immune thrombocytopenia (ITP), myelodysplastic syndromes (MDS), non-APL acute myeloid leukemia (AML), aplastic anemia (AA), multiple myeloma (MM), etc., especially by regulating mesenchymal stem cells and regulatory T cells for the treatment of ITP. ATRA can also increase the expression of CD38 expressed by tumor cells, thus improving the efficacy of daratumumab and CD38-CART. In this review, we focus on the mechanism of action of ATRA, its role in various hematologic diseases, drug combinations, and ongoing clinical trials.

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“… 66 Mutations in splicing factors are acknowledged as significant contributors to myeloid malignancy. 67 , 68 Notably, spliceosome mutations affecting RNA splicing factors are present in over 50% of patients with MDS. 69 Additionally, certain DDX helicases homologous to yeast splicing factors have been confirmed to play an important role in regulating RNA alternative splicing in hematopoietic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional regulation of DEAD-box RNA helicases in hematopoietic malignancies

Fan,

Li,

Pei

et al. 2024

Genes & Diseases

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Targeting low-risk myelodysplastic syndrome with novel therapeutic strategies

Cited by 3 publications

References 94 publications

MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases

MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases

All-trans retinoic acid in hematologic disorders: not just acute promyelocytic leukemia

Post-transcriptional regulation of DEAD-box RNA helicases in hematopoietic malignancies

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