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1. Role of small RNAs, long non-coding RNAs and RNA binding proteins in marrow microenvironment.
The marrow microenvironment (ME) is comprised of several different subtypes including marrow stromal cells, macrophages, endothelial cells, osteoblasts etc. Various ligands critical to hematopoietic stem and progenitor cells (HSPC) are elaborated by several of these cells types. What is not known is how coordinated expression of these factors is effected across different cell types. We hypothesize that common themes of regulation of gene expression are operant through these cell types. We have implemented several genome-wide techniques including HITS-CLIP (High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation) and RNA-Seq to define the role of small RNAs, long non-coding RNAs and RNA-biding proteins in this regulation. Studies are conducted in human stromal cell lines as well as primary human cells from healthy donors.
2. Biology Spliceosome Mutations in Myelodysplastic Syndromes (MDS).
MDS are a heterogeneous group of blood disorders characterized by clonal proliferation of hematopoietic progenitors and low blood counts. Recently, whole genome sequencing has revealed recurring mutations in the RNA-splicing machinery (SF3B1, U2AF1, SRSF2 etc) in up to half the patients with MDS. It is currently unclear how mutations in the highly conserved and ubiquitous splicing machinery can result in the specific phenotype of MDS. We are using a variety of in vivo and in vitro approaches to define the mechanistic basis of these mutations at the molecular, cellular and tissue levels. Studies are performed in collaboration with Alexander C Minella, MD, Northwestern University, Chicago IL.
3. Role of Alternative Polyadenylation (APA) In Hematopoiesis.
Mature mRNA in eukaryotes often chose between several potential polyadenylation signals to terminate transcription and add a non-templated polyadenylated tail (polyA). By increasing or decreasing the length of the 3’ UTR by APA, cells can impose more or less regulation on a transcript (through miRNA or RNA binding proteins). We hypothesize that APA is operant in hematopoietic maturation (specifically, during the maturation of pluripotent CD34+ cells to erythroid maturation). Using next generation sequencing, we are defining patterns of APA during erythroid maturatioin.
4. Musashi Proteins in Aggressive Myeloid Leukemia.
The RNA binding protein Musashi 2 (MSI2) is transcriptionally upregulated in aggressive myeloid leukemia including CML-blast crises and some AML which are resistant to therapies. Although purported to bind to specific sequence motifs in 3’ UTRs of transcripts such as NUMB, unbiased studies have not suggested this to be the mechanism by which MSI2 function in the context of leukemia. Our laboratory is implementing unbiased genome-wide studies including HITS-CLIP to precisely define how MSI2 expression leads to chemoresistance.