Dissecting The Mechanisms of Venetoclax Resistance In Myelodysplastic Syndromes

<p>Myelodysplastic syndromes (MDS) are a class of heterogeneous clonal hematopoietic disorders. The current standard of care for MDS is the hypomethylating agent (HMA)-based therapy. However, only 50 percent of the patients respond, with transient effects and no approved second-line treatment options after their diseases progress to acute myeloid leukemia (AML). The mechanisms that govern HMA failure are unknown. Recently, we unveiled that MDS are maintained and propagated by two different immunophenotypically distinct hierarchical cellular organizations of MDS hematopoietic stem and progenitor cells (HSPCs) through the upregulation of specific survival pathways. This finding allowed us to potentially stratify MDS patients into two subgroups for more effective guided therapy choices.</p> <p>Herein, we provide evidence that one of the two subgroups of MDS patients can achieve a more favorable clinical response to BCL2 inhibition by venetoclax-based therapy. Our preliminary data reveal that MCL1 is one of the determinants of venetoclax resistance in MDS patients and that combining MCL1 inhibition and venetoclax can synergistically eradicate venetoclax-resistant MDS blasts and HSPCs <em>in vitro</em> and reduce tumor burden in patient-derived xenografts. Additionally, in patients enrolled in clinical trials of venetoclax, we observed an expansion of a subset of CD4⁺ T cells with naïve and/or early-activated antigen-experienced phenotype only when the patients responded to venetoclax-based therapy, indicating a possible role of the adaptive immune system in mediating venetoclax response. This study substantiates the reliability of MDS patient stratification based on their immunophenotype in the clinical use of venetoclax-based therapy and assesses the feasibility of targeting MCL1 in venetoclax-resistant MDS patients as a novel therapeutic option to improve their survival.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2021

Authors dc:creator

• Chen, Shuaitong
• <p>0000-0002-8991-2705</p>

Contributors dc:contributor

• Simona Colla
• Marina Konopleva
• Stephanie Watowich

• Myelodysplastic syndromes
• Apoptosis
• BCL2
• MCL1
• Venetoclax
• AMG-176
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1124

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2182