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Structure Function Analysis of Drug Resistance Driver Mutations in Acute Lymphoblastic Leukemia

Zachary Wayne Carpenter

Title:
Structure Function Analysis of Drug Resistance Driver Mutations in Acute Lymphoblastic Leukemia
Author(s):
Carpenter, Zachary Wayne
Thesis Advisor(s):
Rabadan, Raul
Date:
Type:
Theses
Degree:
Ph.D., Columbia University
Department(s):
Pharmacology and Molecular Signaling
Persistent URL:
Abstract:
Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic tumor and is the most common malignancy in children (Horton and Steuber 2014). This disease is characterized by the infiltration of bone marrow by malignant immature lymphoid progenitor cells and is invariably fatal without treatment. Although multi-agent combination chemotherapy is curative in a significant fraction of ALL patients, treatment currently fails in approximately 20% of children and up to 50% of adults with ALL, making relapse and drug resistance the most substantial challenge in the treatment of this disease(Fielding, Richards et al. 2007, Aster and DeAngelo 2013). Understanding what causes treatment failure is of great medical importance as second line therapies also fail in the majority of relapse T-cell ALL (TALL) patients (Fielding, Richards et al. 2007, Aster and DeAngelo 2013). Using next-generation sequencing to compare the genomes of tumors before and after therapy, mutations in gene cytosolic 5’-nucleotidase II (NT5C2) were discovered in 19% of pediatric samples with relapsed T-ALL(Tzoneva, Carpenter et al. 2013). Preliminary structure function analysis and subsequent in vitro experimental nucleotidase activity assays confirmed that these mutations lead to hyperactive NT5C2 protein. Furthermore, NT5C2 mutant proteins conferred resistance to 6-mercaptopurine and 6-thioguanine chemotherapy drugs when expressed in ALL lymphoblasts, suggesting NT5C2 is responsible for the inactivation of nucleoside-analog chemotherapy drugs. In order to assess the ability of these mutations to lead to novel inhibitor schemes, the functional impact of each mutation was analyzed through robust structure function methods. The result of this in silico analysis, is the identification of a potential allosteric regulatory mechanism of negative feedback inhibition never before described. Most notably, the majority of NT5C2 mutations identified have characteristics that suggest they abrogate the function of this proposed mechanism, yielding a novel viable target for the development of allosteric inhibitors specific for constitutively active NT5C2 mutant proteins. Overall these findings support a prominent role for activating mutations in NT5C2 and chemotherapy resistance in ALL, and highlight new avenues for relapsed ALL therapy development in the future.
Subject(s):
Lymphoblastic leukemia in children
Pediatric hematology
Bones--Cancer--Treatment
Bone marrow--Cancer
Drug resistance in cancer cells
Lymphoblastic leukemia
Bioinformatics
Oncology
Pharmacology
Item views
122
Metadata:
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Suggested Citation:
Zachary Wayne Carpenter, , Structure Function Analysis of Drug Resistance Driver Mutations in Acute Lymphoblastic Leukemia, Columbia University Academic Commons, .

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