The noncoding genome presents a largely untapped source of biological insights, including thousands of long noncoding RNA (lncRNA) loci. While some produce bona fide lncRNAs, others exert transcript-independent cis-regulatory effects, and the lack of predictive features renders mechanistic dissection challenging. Here, we describe CTCF-enriched lncRNA loci (C-LNC) as a subclass of functional genetic elements exemplified by MYNRL15, a pan-myeloid leukemia dependency identified by an lncRNA-based CRISPRi screen. MYNRL15 perturbation selectively impairs acute myeloid leukemia (AML) cells over hematopoietic stem / progenitor cells in vitro, and depletes AML xenografts in vivo. Mechanistically, we show that crucial DNA elements in the locus mediate its phenotype, triggering chromatin reorganization and downregulation of cancer dependency genes upon perturbation. Elevated CTCF density distinguishes MYNRL15 and 531 other lncRNA loci in K562 cells, of which 43-54% associate with clinical aspects of AML and 18.4% are functionally required for leukemia maintenance. Curated C-LNC catalogs in other cell types will help refine the search for noncoding oncogenic vulnerabilities in AML and other malignancies.