Long non-coding RNAs (lncRNAs) influence many critical cellular processes such as gene expression. The initiation and progression of myeloid leukemia have thus far been studied mainly within the realm of mutations and/or dysregulation of key protein-coding genes. Whether lncRNAs affect the initiation and progression of malignant myelopoiesis remains to be determined. In addition, elucidating the mechanistic roles of oncogenic lncRNAs will provide the intellectual and experimental framework for developing targeted therapeutics for myeloid leukemia. We have initiated efforts to identify pivotal oncogenic lncRNAs in the pathogenesis of myeloid leukemia. This endeavor has yielded highly promisin...

Read More

Long non-coding RNAs (lncRNAs) influence many critical cellular processes such as gene expression. The initiation and progression of myeloid leukemia have thus far been studied mainly within the realm of mutations and/or dysregulation of key protein-coding genes. Whether lncRNAs affect the initiation and progression of malignant myelopoiesis remains to be determined. In addition, elucidating the mechanistic roles of oncogenic lncRNAs will provide the intellectual and experimental framework for developing targeted therapeutics for myeloid leukemia. We have initiated efforts to identify pivotal oncogenic lncRNAs in the pathogenesis of myeloid leukemia. This endeavor has yielded highly promising candidates including HOTTIP, and this application is aimed at elucidating the mechanistic roles of HOTTIP in myeloid leukemia. We have established the requisite methods and animal models for the successful completion of this project, which include unbiased library screening for candidate lncRNAs, long range chromosome interactions, and mapping lncRNA genomic binding sites. The proposed studies will clarify the role of HOTTIP lncRNA in leukemogenesis, hematopoietic stem cell (HSC) behavior and gene regulation. We will elucidate the molecular mechanism(s) by which HOTTIP regulates chromatin conformation and expression of target genes important for HSC and leukemogenesis using genome-wide chromatin modifications and interactions, transcription profiles, as well as loss-of-function and gain-of-function studies. In addition, we will explore whether this lncRNA can serve as a therapeutic target for AML patients with HOTTIP overexpression. The proposed studies will capitalize on the complementary scientific expertise offered by the UTHSA collaborators. These studies will fill an important knowledge gap concerning oncogenic lncRNAs in myeloid leukemia and their mechanisms of action. Our findings will lead to innovative and novel therapeutic targets/strategies against myeloid leukemia.

Read Less