Beta-Adrenergic Receptor Mediated Transcriptional Dysregulation in Hematopoeitc Stem and Progenitor Cells Leads to Bone Marrow Erythroid Suppresion in Multiple Myeloma Patients - Ex Vivo Investigations
Date of Award
Master of Science (MS)
The sympathetic nervous system (SNS) regulates our body’s involuntary response to stress or harm. Once activated, it releases hormones and neurotransmitters known as catecholamines throughout the body to mediate its recovery. The catecholamines bind to adrenergic receptors located on various cells in a process designated as adrenergic signaling to elicit this response. This process is not always to our benefit. Adverse symptoms such as anemia can result due to adrenergic signaling. Our laboratory previously showed that burn injury triggers adrenergic receptor stimulation resulting in anemia induced by diminished erythropoiesis. The development of anemia in these studies was found to be due to a myeloid bias amongst the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). A myeloid bias entails HSPCs being skewed towards a myeloid lineage commitment versus an erythroid lineage commitment. This results in less development of megakaryocyte-erythrocyte-progenitors (MEPs), which are precursors to mature erythrocytes. The driving factor behind this myeloid commitment was the negative correlation between the transcription factors MAFB and GATA1. It was identified that MAFB expression increased due to adrenergic signaling and this caused GATA1 a crucial erythroid developmental factor to decrease in expression. Through reading several articles we found that a similar anemic response was occurring in multiple myeloma (MM) patients and questioned if our conclusions discovered from our burn studies could be applied. MM is an incurable hematological malignancy characterized by the numerous plasma B cell lesions in the BM. In this study, we established the prevalence of the myeloid bias within the context of MM BM patient samples. Additionally, we confirmed the presence of adrenergic receptors on HSPCs and the predominant receptor subtype that when stimulated leads to a myeloid bias. Lastly, we elucidated the role of MAFB and GATA1 in our MM patients and found that adrenergic stimulation contributes significantly to the myeloid bias. All studies were conducted ex-vivo using BM aspirates that were then placed in cultures containing a growth factor cocktail to enhance the proliferation and survival of our HSPCs. Adrenergic agonist and antagonists along with myeloma cell isolation were used to determine significance of adrenergic stimulation on myeloid bias.
Subramaniam, Vimal Ravi, "Beta-Adrenergic Receptor Mediated Transcriptional Dysregulation in Hematopoeitc Stem and Progenitor Cells Leads to Bone Marrow Erythroid Suppresion in Multiple Myeloma Patients - Ex Vivo Investigations" (2021). Master's Theses. 4380.
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