Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci [RNA-Seq]

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. Transcriptome profiling was performed in K562 and ML-2 cells at early and late timepoints post-MYNRL15 perturbation.