MARCKS is a Critical Downstream Mediator of IL-1-driven AML Progression
Date
8-12-2020 10:40 AM
Abstract
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is genetically heterogeneous, which has made finding lasting treatment options difficult. Of particular interest in the study of AML is the proinflammatory cytokine IL-1, which we have shown to promote the growth of AML cells while suppressing the growth of normal progenitors. An RNA-seq analysis of primary AML samples after IL-1 stimulation was performed and revealed that myristoylated alanine-rich C-kinase substrate (MARCKS) was a differentially expressed gene in AML compared to healthy controls. RNA-seq analysis of 451 primary patient samples also found MARCKS and IL1R1 expressions to be positively correlated. The results of qPCR and western blot experiments revealed that MARCKS mRNA expression, protein level, and activation are increased in primary AML cells compared to healthy controls after IL-1b treatment. To further elucidate the role of MARCKS in AML, genetic knockdown of MARCKS using doxycycline inducible shRNAs was performed in MOLM-14 and THP-1 cell lines. Results indicate that genetic knockdown of MARCKS reduces the viability, growth, and colony formation ability of AML cells in vitro. Understanding the role of MARCKS in IL-1-mediated AML is important for providing a potential avenue for targeted therapy.
Biographies
Alisha Steigerwald
Major: Biology and Public Health
Alisha Steigerwald is a Biology and Public Health double major and is hoping to pursue a minor in Neuroscience. In the spring of 2019, Alisha gave a presentation to the dean of the College of Liberal Arts & Sciences, as well as multiple department chairs, about the need within the PSU community for a minor in Neuroscience. This presentation was well received, a proposal was submitted, and the minor should be available to students in the fall of 2021. Alisha currently conducts research at the OHSU Knight Cancer Institute on acute myeloid leukemia and has previously conducted research on visuospatial processing in individuals with autism at the University of Missouri-Columbia as part of an REU program. Before that, Alisha conducted research on DNA glycosylases in different epigenetic contexts at the Norwegian University of Science and Technology, where she is hoping to return for a Fulbright Fellowship upon graduation. Her research interests are neuroscience and cancer biology, with a particular interest in molecular medicine. On-campus, Alisha is an active member of PSU’s BUILD EXITO program, is part of the leadership team for the Neuroscience Club, serves as a Resident Assistant, and is an Honor College Peer Writing Tutor. During her senior year, Alisha will continue her BUILD EXITO research at OHSU and her job as a Writing Tutor, will serve as a Resident Academic Mentor and Rosenbaum Scholar, and is excited to be President of the Neuroscience Club. After graduation, Alisha is excited to apply for research fellowships and then eventually to MD-PhD programs!
Faculty Mentor: Dr. Anupriya Agarwal
The overarching goal of the Agarwal lab is to identify novel drivers of disease initiation, progression, and drug resistance in leukemia and to ultimately translate these discoveries into treatments for leukemia patients. Specifically, our lab is interested in understanding the composite interplay of genetic events and the tumor microenvironment that are requisite for initiating the growth of preleukemic cells, disease evolution from preleukemic to leukemic stage, and conferring drug resistance. To identify novel pathways of disease initiation and drug resistance, we have developed various functional assays, which we employ in tandem with, single cell transcriptomic, genomic, and proteomic approaches. We take a multidisciplinary approach and utilize various state-of-art techniques to dissect the functional role and therapeutic relevance of identified pathways. Our goal is to use this knowledge to improve the understanding of disease pathobiology and inform the development of novel, molecularly targeted therapies for patients.
Disciplines
Medicine and Health Sciences
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MARCKS is a Critical Downstream Mediator of IL-1-driven AML Progression
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is genetically heterogeneous, which has made finding lasting treatment options difficult. Of particular interest in the study of AML is the proinflammatory cytokine IL-1, which we have shown to promote the growth of AML cells while suppressing the growth of normal progenitors. An RNA-seq analysis of primary AML samples after IL-1 stimulation was performed and revealed that myristoylated alanine-rich C-kinase substrate (MARCKS) was a differentially expressed gene in AML compared to healthy controls. RNA-seq analysis of 451 primary patient samples also found MARCKS and IL1R1 expressions to be positively correlated. The results of qPCR and western blot experiments revealed that MARCKS mRNA expression, protein level, and activation are increased in primary AML cells compared to healthy controls after IL-1b treatment. To further elucidate the role of MARCKS in AML, genetic knockdown of MARCKS using doxycycline inducible shRNAs was performed in MOLM-14 and THP-1 cell lines. Results indicate that genetic knockdown of MARCKS reduces the viability, growth, and colony formation ability of AML cells in vitro. Understanding the role of MARCKS in IL-1-mediated AML is important for providing a potential avenue for targeted therapy.