Investigating the molecular basis of mRNA processing in acute myeloid leukemia
Anna Lee
PhDNYU School of Medicine
Project Term: July 1, 2023 - June 30, 2026
Our research aims to discover key driving factors in leukemia that regulate mRNA processing. The proposed experiments utilize a combination of biochemical, cell-based, and high-throughput sequencing approaches using human leukemia cell lines and primary patient samples. These studies will reveal factors that are essential for leukemic maintenance, uncover molecular details of mRNA processing, and inform the development of novel therapeutic strategies.
Acute myeloid leukemia (AML) is the most common leukemia in adults. It is a devastating progressive disease that is associated with poor prognosis and high mortality, with an overall five-year survival rate of less than 30%. Yet, the treatment of AML has remained largely unchanged over the past three decades, where most patients receive conventional cytotoxic chemotherapies and many eventually relapse. Unfortunately, disease relapse is frequently fatal and bone marrow transplantation is only applicable for select patients; thus, highlighting the urgent need for new targeted treatments. Increasing evidence suggests that myeloid leukemias may be especially dependent on the proteins that bind RNA molecules. Many of these RNA-binding proteins regulate genes and pathways that are essential for the survival of AML cells. One major responsibility of RNA-binding proteins is to regulate the highly-coordinated steps involved in processing RNA, including the “untranslated” regions that do not code for proteins. For years, the untranslated end of mRNAs was considered junk sequence, but it is now known that these untranslated sequences contain important regulatory elements, such that alterations in these regions can have a profound impact on RNA stability and function. Therefore, we analyzed our extensive dataset of bone marrow samples from AML patients and found that malignant AML cells exhibit significant dysregulation in their RNA processing. To determine which proteins contribute to altered RNA processing in AML, we designed screens to identify regulators of RNA processing that are also essential for AML cell survival. Our proposal utilizes a combination of biochemical, cell-based, and cutting-edge sequencing approaches to determine how these regulators alter RNA processing and to characterize how dysregulated RNA processing promotes AML. Through our studies, we will uncover the molecular details of RNA processing that are hijacked by cancer cells to drive leukemia and reveal new therapeutic strategies for treating this aggressive blood cancer.