Proteogenomic insights into the nature of chemoresistance in Chronic Myelogenous Leukemia

Brett M Noel, Purdue University

Abstract

Chronic Myelogenous Leukemia (CML) is a hematopoietic cancer caused by the formation of the Philadelphia chromosome, a reciprocal translocation of the ABL1 oncogene on chromosome 9, and the breakpoint cluster region gene (BCR) chromosome 22, resulting in the BCR-ABL oncoprotein. BCR-ABL is a constitutively active tyrosine kinase that regulates cell growth and differentiation, leading to uncontrolled cell proliferation by deregulating downstream signaling pathways. A revolution in cancer treatment was ushered in with the introduction of imatinib mesylate (Gleevec®), an ATP-competitive inhibitor specific to BCR-ABL which traps the oncoprotein in its inactive conformation, leading to its degradation. Imatinib validated small-molecule kinase inhibitors as promising candidates for cancer therapy. However, a small but significant portion of CML patients is intrinsically resistant to imatinib, and others develop resistance over time. Mutations in the kinase domain preventing drug binding are partially responsible for resistance, but in many patients, no mutations are present. Second-generation BCR-ABL TKIs nilotinib and dasatinib have been developed which inhibit BCR-ABL even in the presence of kinase domain mutations conferring resistance to imatinib, but resistance to both second-generation tyrosine kinase inhibitors (TKIs) has been reported. We have developed lines of K562 cells resistant to imatinib (K562-IR), nilotinib (K562-NR), and dasatinib (K562-DR), respectively. We used a proteogenomic approach, bridging transcriptomics with proteomics to attempt to unravel the mechanisms underlying TKI-resistance and identify potential biomarkers of TKI-resistance in CML. We identified significant increased protein expression in proteins involved in cell proliferation, and a reduction of the proteins involved in protein translation across all three TKI-resistant cell lines, and also identified novel fusion genes present in our TKI-resistant cell lines that could potentially serve as biomarkers of acquired resistance.

Degree

Ph.D.

Advisors

Parker, Purdue University.

Subject Area

Molecular biology|Genetics|Biochemistry|Oncology

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