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Gopal, Aparna

University of British Columbia

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are among the most common hematological malignancies. While a number of therapies have been approved for their treatment, resistance to therapy remains a major challenge. The prognosis for patients who are therapy resistant is very poor with supportive care being the mainstay of their clinical management. This highlights the need to identify both predictors for therapy response in patients and new therapeutic targets. In this dissertation I use a mix of mouse bone marrow transplant models and human patient sample analysis to better understand the pathophysiology of MDS and AML and therapy resistance in patients. Innate immune dysregulation in MDS has been an active area of research and targeting components of this pathway as therapeutic targets have been explored. Using mouse bone marrow transplantation assays, I reveal novel roles of the innate immune adaptor protein, TIRAP in suppressing all three arms of hematopoiesis. TIRAP expression promotes upregulation of Ifnγ, leading to myelosuppression through release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifnγ blocks Hmgb1 release and is sufficient to reverse the endothelial defect and restore myelopoiesis. Hmgb1 being a highly targetable molecule holds potential to be studied as a therapeutic target for patients with MDS. 5-Azacytidine forms part of the core treatment modality for a vast number of patients with MDS and AML. However, only ~50% of patients respond to 5-Azacytitine. The dynamics of 5-Azacytidine response is slow and there has been no way of predicting who would respond to 5-Azacytidine without therapy initiation. To address this need, using human patient bone marrow samples taken before therapy initiation, I characterized the rare leukemic stem cell compartment to identify different cell states between responders and non-responders. This cell state is in part determined by differential binding of the chromatin architecture protein ZNF143 which induces transcriptional programs that determine the cell state; HOXB being one of them. Finally on account of this characterization, I identified a clinically applicable biomarker, expression of cell surface protein CD45RA, that is able to predict response to 5-Azacytidine.

Text

2025-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88579

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/