Investigating Mechanisms of Leukemic Self-Renewal in Acute Myeloid Leukemia
Abstract
About the Principal Investigator: My career goal is to succeed as an independent scientist in the study of cancer biology. I am pursuing research in aggressive blood cancers, where great efforts are needed to improve current outcomes. Particularly, there is an urgent need to bring new therapies to children, adolescents, and young adults who suffer from acute myeloid leukemia (AML): current approaches are not effective for many patients and may render long-term debilitating effects. With this motivation and the guidance of my mentors, I have formulated hypotheses that address a notable question in the field of AML: how can we target the cellular properties that drive leukemia progression? The experimental strategy of this proposal is geared to discover important mechanisms that sustain leukemia stem cells, which may be therapeutically tractable. The resources that my Institution provides at the Sanford Burnham Prebys (SBP) National Cancer Institute-Designated Cancer Center in the context of the San Diego life-science cluster are unique and optimal for the implementation of my proposal. My mentors are experienced and committed to my training, motivating me to bring this application forward. This award will enable me to strengthen my training in the technical and professional realms. Thus, I will further my research during my graduate studies and beyond, into the next stage of my career. Scientific objective and rationale: Leukemia is a blood cancer that affects both adult and pediatric patients. Notably, it is the most common cancer in pediatric patients, accounting for about 30% of diagnoses. While survival outcomes have generally improved for leukemia patients over the past decades, many relapse after therapy or do not respond at all. These clinical cases drive a need to discover better drugs that can tackle this disease effectively and in a targeted manner, to avoid debilitating consequences for the patient. Our lab focuses on the investigation of a subset of AML termed “AF10-rearranged leukemia” (AF10-R). We are interested in this subset because AF10-R patients face a very aggressive disease, with bleak prospects of survival. A way to resolving this clinical outcome is to understand the molecular profile of leukemia cells. This strategy yields insights into what makes malignant cells vulnerable, compared to healthy cells. Leukemia cells in AF10-R patients acquire a genetic change in their DNA that establishes stem cell-like or “stemness” programs that take control of cell growth and division. The stemness program is of particular interest to us, because most normal blood cells can only give rise to a finite number of daughter cells. However, once stemness pathways are activated, leukemia cells can be rendered virtually immortal, capable of exerting self-renewal. To find the key factors that drive self-renewal, we conducted innovative experiments in which we perturbed genes and looked at the effects in leukemia cells. We evaluated the effects of gene perturbation by measuring the expression of genes that are directly linked to self-renewal. Our research found unrecognized factors that potentially drive this malignant program and could lead to the development of new drugs. To advance our findings, we will extensively characterize the biochemical and functional details of our potential regulators of self-renewal. This proposal addresses the experiments required to do so, taking into consideration rigorous criteria to identify ways to selectively modulate the self-renewal program of leukemia cells so as not to harm normal blood cells. To achieve this, our approaches include complex mouse experiments that have been outlined as a gold-standard to assess self-renewal. We anticipate that our findings may inform research efforts in a variety of AML subtypes besides AF10-R, so we will evaluate our results in diverse genetic settings that mimic those found in patients. Beyond the scope of this proposal, our findings may give insigh
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010703
Entities
People
- Karina Barbosa Guerra
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army