We begin 2021 with happy news! Dr. rer. nat. Michelle Ng has graduated from the HBRS Molecular Medicine PhD program with top honours (summa cum laude). Her thesis is titled “Discovery of functional long noncoding RNA loci in acute myeloid leukemia using CRISPR/Cas9 technologies”.
The 98% of the genome that does not encode protein presents a largely untapped source of new biological insights and a vastly expanded search space for therapeutically actionable elements. These include, among others things, enhancers, topological domain boundaries, and tens of thousands of long noncoding RNAs (lncRNAs), all of which have been implicated in meta-omic control and cancer. For acute myeloid leukemia (AML) – the treatment of which has not fundamentally changed since the 1970s – the noncoding genome provides a unique opportunity for biologic and therapeutic discovery. However, despite recent advances, the contribution of noncoding regions to the pathophysiology of AML remains unclear.
Starting with lncRNA expression profiles from normal hematopoietic cells and AML patient samples, Michelle screened these lncRNAs for novel leukemia vulnerabilities, and uncovered myeloid leukemia noncoding regulatory locus on chromosome 15, or MYNRL15, as a pan-myeloid leukemia dependency. Using high- and low-throughput CRISPR/Cas9 approaches, she demonstrated that the loss of regulatory DNA elements in the locus, rather than its transcriptional products, mediates its perturbation phenotype, triggering the suppression of oncogenic pathways, dysregulation of chromosome 15 neighborhoods, and formation of a tumor-suppressive long-range chromatin interaction. MYNRL15 is characterized by elevated CTCF occupancy, low abundance, and short span – features shared by hundreds of lncRNA loci in the human genome, half of which associate with clinical aspects in AML patient cohorts. Such loci may embody a new class of functional noncoding elements with profound implications for AML and cancer pathophysiology, as exemplified by MYNRL15.
Michelle is currently staying on as a postdoctoral fellow, in order to complete the MYNRL15 manuscript.