Dataset Information

Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.

ABSTRACT:

Background

Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic malignancy that arises from hematopoietic stem and progenitor cells (HSPCs). Patients with CMML are frequently treated with epigenetic therapeutic approaches, in particular the hypomethylating agents (HMAs), azacitidine (Aza) and decitabine (Dec). Although HMAs are believed to mediate their efficacy via re-expression of hypermethylated tumor suppressors, knowledge about relevant HMA targets is scarce. As silencing of tumor-suppressive micro-RNAs (miRs) by promoter hypermethylation is a crucial step in malignant transformation, we asked for a role of miRs in HMA efficacy in CMML.

Results

Initially, we performed genome-wide miR-expression profiling in a Kras^G12D-induced CMML mouse model. Selected candidates with prominently decreased expression were validated by qPCR in CMML mice and human CMML patients. These experiments revealed the consistent decrease in miR-125a, a miR with previously described tumor-suppressive function in myeloid neoplasias. Furthermore, we show that miR-125a downregulation is caused by hypermethylation of its upstream region and can be reversed by HMA treatment. By employing both lentiviral and CRISPR/Cas9-based miR-125a modification, we demonstrate that HMA-induced miR-125a upregulation indeed contributes to mediating the anti-leukemic effects of these drugs. These data were validated in a clinical context, as miR-125a expression increased after HMA treatment in CMML patients, a phenomenon that was particularly pronounced in cases showing clinical response to these drugs.

Conclusions

Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.

SUBMITTER: Berg JL

PROVIDER: S-EPMC7789782 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.

Berg Johannes Lorenz JL Perfler Bianca B Hatzl Stefan S Mayer Marie-Christina MC Wurm Sonja S Uhl Barbara B Reinisch Andreas A Klymiuk Ingeborg I Tierling Sascha S Pregartner Gudrun G Bachmaier Gerhard G Berghold Andrea A Geissler Klaus K Pichler Martin M Hoefler Gerald G Strobl Herbert H Wölfler Albert A Sill Heinz H Zebisch Armin A

Clinical epigenetics 20210106 1

<h4>Background</h4>Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic malignancy that arises from hematopoietic stem and progenitor cells (HSPCs). Patients with CMML are frequently treated with epigenetic therapeutic approaches, in particular the hypomethylating agents (HMAs), azacitidine (Aza) and decitabine (Dec). Although HMAs are believed to mediate their efficacy via re-expression of hypermethylated tumor suppressors, knowledge about relevant HMA targets is scarce. As sil ...[more]

PMID: 33407852

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Project description:Background: The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly investigated. Objectives: We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting. Design: Observational study. Methods: We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection. Results: The rate of infection was 1.2 per patient/year. Next-cycle delay (p = 0.001) and hospitalizations (p = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 [95% confidence interval (CI) = 1.26–1.84], p < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 [3–8] versu 8 [5–16], p < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 [95% CI = 1.09–1.88], p = 0.01), bone marrow blasts ⩾30% (HR = 2.13 [95% CI = 1.14–3.96], p = 0.01), adverse cytogenetics (HR = 1.70 [95% CI = 1.30–2.24], p < 0.001), and platelet count <50 × 109/l (HR = 1.69 [95% CI = 1.3–2.2], p < 0.001). BM blasts >20% (HR = 1.57 [95% CI = 1.19–2.01], p < 0.001) and adverse cytogenetics (HR = 1.7 [95% CI = 1.35–2.14], p < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 [95% CI = 0.51–0.82], p < 0.001) and higher platelet count (HR = 0.997 [95% CI = 0.996–0.998], p = 0.016) protected from it. Conclusion: HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients.

Dataset Information

Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.

Background

Results

Conclusions

Publications

Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.

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