Identifying Novel Therapeutic Targets in Acute Myeloid Leukemia

Embargo until
2021-12-01
Date
2017-07-14
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Publisher
Johns Hopkins University
Abstract
Though most acute myeloid leukemia (AML) patients achieve complete remissions (CRs) with standard induction chemotherapy, the majority subsequently relapse and die from the disease. My thesis studies revolved around better understanding the biology of AML with an eye to prevent these relapses. I focused on identifying therapeutic targets that have the potential to overcome deficits in the current disease treatment paradigm through two different approaches. Chapter 2 reveals findings from a project aimed at identifying novel antigens on AML cells that could serve as therapeutic targets. Using the sera of AML patients from an immunotherapy trial studying a vaccine composed of a GM-CSF-secreting K562 leukemia cell line combined with irradiated autologous AML blasts, we analyzed the composition of antibodies found in AML patient serum versus those found in normal donor serum to identify useful therapeutic targets. Though this led to the identification of antibodies against two potential novel AML antigens, both were ruled out based on their lack of expression in AML patient cells. In Chapter 3, I discuss major findings from my second project attempting to validate previously proposed leukemia stem cell (LSC) specific targets. Using a novel means to identify LSCs relying on the most immature cell phenotype present within a patient’s leukemia, we analyzed LSC-marker expression across leukemia subtypes. Not unexpectedly, the phenotypes of LSCs varied across these subtypes. Ultimately, from those already proposed LSC-specific markers, CD123 and CLL-1 proved to be the most promising as therapeutic targets in AML given their consistently differential expression from normal hematopoietic stem cells (HSCs). Ongoing clinical trials focusing on anti-CD123 therapies as post-remission therapy for AML are underway and will provide definitive insights into the therapeutic potential of CD123 on AML cells.
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Keywords
leukemia, leukemia stem cells, acute myeloid leukemia
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