Similar Datasets
Project description:The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide functional transcripts, others exert transcript-independent regulatory effects, and the lack of predictive features renders mechanistic dissection a major challenge. Here, we describe MYNRL15: a noncoding regulatory locus on chromosome 15 and pan-myeloid leukemia dependency identified by a CRISPR screen of lncRNA signatures from hematopoietic stem and progenitor cells (HSPCs) and acute myeloid leukemia (AML) samples We demonstrate that the loss of cis-regulatory DNA elements in the locus, rather than its transcriptional products, drives its perturbation phenotype, triggering a global downregulation of oncogenic pathways, coordinated dysregulation of chromosome 15 neighborhoods, and formation of a tumor-suppressive, long-range chromatin interaction with the base of a distal loop. In addition, MYNRL15 perturbation selectively impaired primary AML blasts over normal HSPCs in vitro, and depleted patient-derived xenografts in vivo, providing evidence for oncogenic vulnerabilities at chromatin-regulating, noncoding loci. MYNRL15 is characterized by elevated CTCF binding, low expression, and short span - features shared by hundreds of lncRNA genes, nearly half of which associate with clinical aspects in AML patient cohorts. We propose these as a new class of functional genetic elements carrying both therapeutic potential for AML and profound implications for cancer pathophysiology in general, as exemplified by MYNRL15.
2023-10-04 | GSE172238 | GEO
Project description:he noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide functional transcripts, others exert transcript-independent regulatory effects, and the lack of predictive features renders mechanistic dissection a major challenge. Here, we describe MYNRL15: a noncoding regulatory locus on chromosome 15 and pan-myeloid leukemia dependency identified by a CRISPR screen of lncRNA signatures from hematopoietic stem and progenitor cells (HSPCs) and acute myeloid leukemia (AML) samples We demonstrate that the loss of cis-regulatory DNA elements in the locus, rather than its transcriptional products, drives its perturbation phenotype, triggering a global downregulation of oncogenic pathways, coordinated dysregulation of chromosome 15 neighborhoods, and formation of a tumor-suppressive, long-range chromatin interaction with the base of a distal loop. In addition, MYNRL15 perturbation selectively impaired primary AML blasts over normal HSPCs in vitro, and depleted patient-derived xenografts in vivo, providing evidence for oncogenic vulnerabilities at chromatin-regulating, noncoding loci. MYNRL15 is characterized by elevated CTCF binding, low expression, and short span - features shared by hundreds of lncRNA genes, nearly half of which associate with clinical aspects in AML patient cohorts. We propose these as a new class of functional genetic elements carrying both therapeutic potential for AML and profound implications for cancer pathophysiology in general, as exemplified by MYNRL15.
2023-10-04 | GSE172237 | GEO
Project description:The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide functional transcripts, others exert transcript-independent regulatory effects, and the lack of predictive features renders mechanistic dissection a major challenge. Here, we describe MYNRL15: a noncoding regulatory locus on chromosome 15 and pan-myeloid leukemia dependency identified by a CRISPR screen of lncRNA signatures from hematopoietic stem and progenitor cells (HSPCs) and acute myeloid leukemia (AML) samples We demonstrate that the loss of cis-regulatory DNA elements in the locus, rather than its transcriptional products, drives its perturbation phenotype, triggering a global downregulation of oncogenic pathways, coordinated dysregulation of chromosome 15 neighborhoods, and formation of a tumor-suppressive, long-range chromatin interaction with the base of a distal loop. In addition, MYNRL15 perturbation selectively impaired primary AML blasts over normal HSPCs in vitro, and depleted patient-derived xenografts in vivo, providing evidence for oncogenic vulnerabilities at chromatin-regulating, noncoding loci. MYNRL15 is characterized by elevated CTCF binding, low expression, and short span - features shared by hundreds of lncRNA genes, nearly half of which associate with clinical aspects in AML patient cohorts. We propose these as a new class of functional genetic elements carrying both therapeutic potential for AML and profound implications for cancer pathophysiology in general, as exemplified by MYNRL15.
2023-10-04 | GSE172236 | GEO
Project description:The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide functional transcripts, others exert transcript-independent regulatory effects, and the lack of predictive features renders mechanistic dissection a major challenge. Here, we describe MYNRL15: a noncoding regulatory locus on chromosome 15 and pan-myeloid leukemia dependency identified by a CRISPR screen of lncRNA signatures from hematopoietic stem and progenitor cells (HSPCs) and acute myeloid leukemia (AML) samples We demonstrate that the loss of cis-regulatory DNA elements in the locus, rather than its transcriptional products, drives its perturbation phenotype, triggering a global downregulation of oncogenic pathways, coordinated dysregulation of chromosome 15 neighborhoods, and formation of a tumor-suppressive, long-range chromatin interaction with the base of a distal loop. In addition, MYNRL15 perturbation selectively impaired primary AML blasts over normal HSPCs in vitro, and depleted patient-derived xenografts in vivo, providing evidence for oncogenic vulnerabilities at chromatin-regulating, noncoding loci. MYNRL15 is characterized by elevated CTCF binding, low expression, and short span - features shared by hundreds of lncRNA genes, nearly half of which associate with clinical aspects in AML patient cohorts. We propose these as a new class of functional genetic elements carrying both therapeutic potential for AML and profound implications for cancer pathophysiology in general, as exemplified by MYNRL15.
2023-10-04 | GSE172235 | GEO
Project description:Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci
| PRJNA722507 | ENA
Project description:Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci [CUT&RUN]
| PRJNA722505 | ENA
Project description:Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci [capture-C]
| PRJNA722509 | ENA
Project description:Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci [ATAC-Seq]
| PRJNA722506 | ENA
Project description:Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci [RNA-Seq]
| PRJNA722508 | ENA
Project description: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.
| S-EPMC10520325 | biostudies-literature