Dataset Information

Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15.

ABSTRACT: The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo.

SUBMITTER: Ng M

PROVIDER: S-EPMC10520325 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus <i>MYNRL15</i>.

Ng Michelle M Verboon Lonneke L Issa Hasan H Bhayadia Raj R Vermunt Marit Willemijn MW Winkler Robert R Schüler Leah L Alejo Oriol O Schuschel Konstantin K Regenyi Eniko E Borchert Dorit D Heuser Michael M Reinhardt Dirk D Yaspo Marie-Laure ML Heckl Dirk D Klusmann Jan-Henning JH

iScience 20230907 10

The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified <i>MYNRL15</i> as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism ...[more]

PMID: 37766974

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Project description:PurposeOptimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene mutations. Long noncoding RNA (lncRNA) transcripts have been shown to associate with and mediate malignant phenotypes in acute myeloid leukemia (AML) but have not been comprehensively evaluated in pAML.MethodsTo identify lncRNA transcripts associated with outcomes, we evaluated the annotated lncRNA landscape by transcript sequencing of 1,298 pediatric and 96 adult AML specimens. Upregulated lncRNAs identified in the pAML training set were used to establish a regularized Cox regression model of event-free survival (EFS), yielding a 37 lncRNA signature (lncScore). Discretized lncScores were correlated with initial and postinduction treatment outcomes using Cox proportional hazards models in validation sets. Predictive model performance was compared with standard stratification methods by concordance analysis.ResultsTraining set cases with positive lncScores had 5-year EFS and overall survival rates of 26.7% and 42.7%, respectively, compared with 56.9% and 76.3% with negative lncScores (hazard ratio, 2.48 and 3.16; P < .001). Pediatric validation cohorts and an adult AML group yielded comparable results in magnitude and significance. lncScore remained independently prognostic in multivariable models, including key factors used in preinduction and postinduction risk stratification. Subgroup analysis suggested that lncScores provide additional outcome information in heterogeneous subgroups currently classified as indeterminate risk. Concordance analysis showed that lncScore adds to overall classification accuracy with at least comparable predictive performance to current stratification methods that rely on multiple assays.ConclusionInclusion of the lncScore enhances predictive power of traditional cytogenetic and mutation-defined stratification in pAML with potential, as a single assay, to replace these complex stratification schemes with comparable predictive accuracy.

Project description:BackgroundNumerous studies have probed the deregulation of the long noncoding RNA AB073614 and FER1L4, which have been discovered in a variety of cancers. However, the precise expression pattern of these lncRNAs and their clinical implications in acute myeloid leukemia (AML) remain elusive. Considering the involvement of the PI3K axis in AML pathogenesis, an investigation into the expression of AB073614 and FER1L4 targets of this pathway has been proposed, aiming to elucidate a potential mechanism underlying AML development.MethodsThe expression levels of lncRNA AB073614 and FER1L4 were assessed in 30 newly diagnosed AML patients and 12 healthy individuals using quantitative reverse transcription-polymerase chain reaction techniques. A statistical analysis was conducted to determine the association of AB073614 and FER1L4 expression levels with clinicopathological features.ResultsA significant upregulation of AB073614 was observed in AML patients compared to the control group (p < 0.05). Moreover, a notable increase in AB073614 expression levels coincided with a significant reduction in FER1L4 expression levels in AML samples (p < 0.05). The diagnostic value of these lncRNAs was validated using the receiver operating characteristic (ROC) curve and area under the curve (AUC) calculations. Sensitivity values of AB073614 and FER1L4 gene expression were 96.7% and 100%, respectively, using cut-off relative quantification of 1.045 and 0.770. Additionally, specificity values were observed to be 100%.ConclusionsThe present study indicates that AB073614 and FER1L4 might serve as prognosis biomarkers in AML patients. However, further detailed examinations in this field are warranted. It is proposed that the likely mechanism of imbalanced PI3K and PTEN activity, triggered by the deregulation of AB073614 and FER1L4, may have a crucial role in AML pathogenesis. Any component of this pathway could potentially serve as a new target for more insightful treatment approaches.

Dataset Information

Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15.

Publications

Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus <i>MYNRL15</i>.

Similar Datasets

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