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Simple Summary: Although childhood acute lymphoblastic leukemia (chALL) management is considered as one of the success stories in modern clinical oncology, the increased incidence of relapse in high-risk patients and the severe toxicity/long-term health effects due to chemotherapy intensity highlight the need for further improvements in patients' risk stratification and personalized management. Synthetic glucocorticoids (GCs) are the core agents in chALL chemotherapy, exerting their role through the nuclear glucocorticoid receptor (GR), while GAS5 lncRNA suppresses the GCs-GR axis through binding to GR's DNA binding domain. The objective of the study was the evaluation of GAS5 prognostic utility in chALL. GAS5 overexpression was strongly associated with a higher risk for short-term relapse and poor treatment outcome, independently of patients' clinicopathological data. Moreover, "GAS5-including" multivariate models resulted in superior risk stratification and clinical benefit for disease prognosis, supporting precision medicine decisions in chALL. Glucocorticoids (GCs) remain the cornerstone of childhood acute lymphoblastic leukemia (chALL) therapy, exerting their cytotoxic effects through binding and activating of the glucocorticoid receptor (GR). GAS5 lncRNA acts as a potent riborepressor of GR transcriptional activity, and thus targeting GAS5 in GC-treated chALL could provide further insights into GC resistance and support personalized treatment decisions. Herein, to study the clinical utility of GAS5 in chALL prognosis and chemotherapy response, GAS5 expression was quantified by RT-qPCR in bone marrow samples of chB-ALL patients at diagnosis (n = 164) and at end-of-induction (n = 109), treated with ALL-BFM protocol. Patients' relapse and death were used as clinical end-points for survival analysis. Bootstrap analysis was performed for internal validation, and decision curve analysis assessed the clinical net benefit for chALL prognosis. Our findings demonstrated the elevated GAS5 levels in blasts of chALL patients compared to controls and the significantly higher risk for short-term relapse and poor treatment outcome of patients overexpressing GAS5, independently of their clinicopathological data. The unfavorable prognostic value of GAS5 overexpression was strongly validated in the high-risk/stem-cell transplantation subgroup. Finally, multivariate models incorporating GAS5 levels resulted in superior risk stratification and clinical benefit for chALL prognostication, supporting personalized prognosis and precision medicine decisions in chALL. [ABSTRACT FROM AUTHOR]

Simple Summary: Myelofibrosis (MF) displays the worst prognosis among Philadelphia-negative chronic myeloproliferative neoplasms. There is no curative therapy for MF, except for bone marrow transplantation, which however has a consistent percentage of failure. There is thus an urgent need of novel biomarkers to complement current stratification models and to enable better management of patients. To address this issue, we herein measured the plasma levels of several long noncoding RNAs (lncRNAs). Circulating lncRNAs has been already largely described as potential non-invasive biomarkers in cancers. In our study we unveiled that LINC01268, MALAT1 (both p < 0.0001) and GAS5 (p = 0.0003) plasma levels are significantly higher in MF patients if compared with healthy donors, and their increased plasma levels correlate with several detrimental features in MF. Among them, LINC01268 is an independent variable for both OS (p = 0.0297) and LFS (p = 0.0479), thus representing a putative new biomarker suitable for integrate contemporary prognostic models. Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients (n = 143), compared to healthy controls (n = 65). Among these, high levels of LINC01268, MALAT1 or GAS5 correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of LINC01268 (p = 0.0018), GAS5 (p = 0.0008) or MALAT1 (p = 0.0348) are also associated with a poor overall-survival while high levels of LINC01268 correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of LINC01268 is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients' cohort, it could be used for further studies to design an updated classification model for MF patients. [ABSTRACT FROM AUTHOR]