Molecular Characterization of Long Non-Coding RNA CASC15 in Leukemogenesis

High throughput transcriptome sequencing has uncovered a previously uncharacterized layer of gene regulation by long non-coding RNAs (lncRNAs). LncRNAs are characterized by capped, polyadenylated, and spliced transcripts that lack an open reading frame. Despite the similarities in their genetic organization, they play variety of roles at the cellular level, including regulation of transcription and translation, leading to alterations in gene expression. One of these functions is the regulation of expression of chromosomally adjacent genes. Here, we examined the function of the lncRNA CASC15 that was originally discovered as being dysregulated in in ETV6-RUNX1-translocated B-acute lymphoblastic leukemia. Enforced expression of CASC15 in hematopoietic stem and progenitor cells led to a myeloid bias in development with an overall decrease in engraftment and colony formation. Conversely, using a CRISPR-based approach, CASC15 deletion skewed hematopoietic cell progenitors towards a B cell fate. CASC15 was also demonstrated to regulate cellular survival, proliferation, and the expression of its chromosomally adjacent gene, SOX4. Differentially regulated genes following CASC15 knockdown in cell lines were enrichment for predicted transcriptional targets of the Yin and Yang-1 (YY1) transcription factor. To further characterize this, we queried a functional relationship between YY1 and CASC15. Interestingly, we found that YY1 interacts with CASC15, and that CASC15 enhanced YY1-mediated transcription at the SOX4 promoter. Together these studies represent some of the first functional characterizations of lncRNAs in leukemia and highlight the importance of non-coding regulatory mechanisms in malignant hematopoiesis.