Off-Target Inhibition of Human Dihydroorotate Dehydrogenase (DHODH) Highlights Challenges in the Development of Fat Mass and Obesity-Associated Protein (FTO) Inhibitors.

FTO, an -methyladenosine (mA) and ,2'--dimethyladenosine (mA) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (DHODH).

WTAP and mA-modified circRNAs modulation during stress response in acute myeloid leukemia progenitor cells.

N-methyladenosine (mA) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML).

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection.

Background: Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A).

Sorcin promotes migration in cancer and regulates the EGF-dependent EGFR signaling pathways.

The epidermal growth factor receptor (EGFR) is one of the main tumor drivers and is an important therapeutic target for many cancers. Calcium is important in EGFR signaling pathways. Sorcin is one of the most important calcium sensor proteins, overexpressed in many tumors, that promotes cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, malignant progression and resistance to chemotherapeutic drugs.

Circular RNAs Activity in the Leukemic Bone Marrow Microenvironment.

Acute myeloid leukemia (AML) is a hematological malignancy originating from defective hematopoietic stem cells in the bone marrow. In spite of the recent approval of several molecular targeted therapies for AML treatment, disease recurrence remains an issue. Interestingly, increasing evidence has pointed out the relevance of bone marrow (BM) niche remodeling during leukemia onset and progression.

Long Non-Coding RNAs in the Cell Fate Determination of Neoplastic Thymic Epithelial Cells.

Thymic Epithelial Tumors (TETs) arise from epithelial cells of the thymus and are very rare neoplasms comprising Thymoma, Thymic carcinoma, and Thymic Neuroendocrine tumors that still require in-depth molecular characterization. Long non-coding RNAs (lncRNAs) are emerging as relevant gene expression modulators involved in the deregulation of several networks in almost all types of human cancer, including TETs. LncRNAs act at different control levels in the regulation of gene expression, from transcription to translation, and modulate several pathways relevant to cell fate determination under normal and pathological conditions.

New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients.

METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors.

Background: Thymic epithelial tumors (TETs) are rare neoplasms, originating from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined, and a deeper molecular characterization could result in a relevant advance in their management, greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (mA) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in cell differentiation and carcinogenesis.

Circulating microRNAs from the Molecular Mechanisms to Clinical Biomarkers: A Focus on the Clear Cell Renal Cell Carcinoma.

microRNAs (miRNAs) are emerging as relevant molecules in cancer development and progression. MiRNAs add a post-transcriptional level of control to the regulation of gene expression. The deregulation of miRNA expression results in changing the molecular circuitry in which miRNAs are involved, leading to alterations of cell fate determination.

LINC00174 is a novel prognostic factor in thymic epithelial tumors involved in cell migration and lipid metabolism.

Long non-coding RNAs are emerging as new molecular players involved in many biological processes, such as proliferation, apoptosis, cell cycle, migration, and differentiation. Their aberrant expression has been reported in variety of diseases. The aim of this study is the identification and functional characterization of clinically relevant lncRNAs responsible for the inhibition of miR-145-5p, a key tumor suppressor in thymic epithelial tumors (TETs).

Emerging role of secreted miR-210-3p as potential biomarker for clear cell Renal Cell Carcinoma metastasis.

Background: MicroRNAs (miRNAs) are emerging as promising molecules in the diagnosis, prognosis and treatment of urological tumours. Recently, our group performed two independent studies highlighting that miR-210-3p may be a useful biomarker not only for diagnosis but also for post-surgery clear cell Renal Cell Carcinoma (ccRCC) management.

Objective: The aim of this study is to further explore the effectiveness of miRNA as non-invasive biomarker for clinical outcomes and ccRCC response to the treatment.