University of Texas Health Science Center at Houston
Effects of Pharmacological and Genetic Disruption of Chemokine Receptor Cxcr4 In B-Cell Acute Lymphoblastic Leukemia
Abstract
dc:description.abstract<p>The CXCR4 chemokine receptor plays a pivotal role in homing and retention of B-cell Acute Lymphoblastic Leukemia cells to bone marrow niches. The bone marrow stromal cells (BMSCs) constitutively secrete the CXCR4 ligand CXCL12, thus attracting leukemia cells and protecting them from cytotoxic drugs, a mechanism that might be responsible for minimal residual disease after conventional chemotherapy against B-ALL. Indeed, in this study we observed that B-ALL cells that had migrated beneath the BMSCs were highly resistant to chemotherapeutic drugs. Inhibition of CXCR4 to disrupt this interaction presents itself as an attractive target to overcome bone marrow derived drug resistance mechanisms. We observed that not only did pharmacological inhibition of CXCR4 significantly reduce chemotaxis and migration of B-ALL cells beneath BMSCs, it significantly enhanced drug-induced cytotoxicity of Cyclophosphamide, Dexamethasone and Vincristine. Furthermore, we report an <em>in vitro</em> and <em>in vivo</em> CXCR4 genetic deletion model of B-ALL cells generated using the CRISPR-Cas9 gene editing technology. The CXCR4 Knockout cells display defective chemotaxis and migration beneath BMSCs. Moreover, the BMSCs fail to rescue the CXCR4 Knockout cells from drug-induced cytotoxicity. Also, non-irradiated NOD/SCID/IL-2rγnull mice injected with CXCR4 Knockout cells displayed significantly lower leukemia burden, bone marrow infiltration and survival as compared to mice injected with CXCR4 wild type cells. Collectively, these findings provide a rationale for clinical targeting of CXCR4 in patients with B-ALL.</p>
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy (PhD)
- Level thesis:degree_level
- Dissertation (PhD)
- Year dc:date.available
- 2015
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Randhawa, Shubhchintan
- Contributors dc:contributor
-
- Jan A. Burger
- Richard E. Davis
- Zeev Estrov
Subjects
dc:subject × 8Identifiers
dc:identifier.*- Repository record dc:identifier
- https://digitalcommons.library.tmc.edu/utgsbs_dissertations/634
- OAI identifier oai:identifier
- oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1669