Graduation Date

Summer 8-19-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Dr. Kai Fu

Second Advisor

Dr. John Chan

Abstract

Extranodal natural killer/T-cell lymphomas (NKTCL) are uncommon lymphomas with poor prognosis. In order to gain a better understanding of the molecular pathogenesis of NKTCL, we obtained and compared the global gene expression profile, global somatic mutation profile, and global methylation profile of normal NK cells, malignant NK cell lines, and NKTCL patient samples. We showed that the JAK-STAT pathway was constitutively activated in NKTCL through the cooperation between activation of signal transducer and activator of transcription proteins (STATs) via activating mutations and inactivation of STAT suppressor protein suppressor of cytokine signaling 6 (SOCS6) through promoter hypermethylation. Activating STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor or by expressing exogenous SOCS6. Molecular modelling and surface plasmon resonance measurements of the N642H STAT5B mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant protein. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. We also showed that Blimp1, a tumor suppressor gene frequently inactivated in NKTCL by the combination of allelic deletion and promoter hypermethylation, has an effect on NK cell homeostasis, maturation and function using a NK-lineage specific Blimp1-knockout mouse model. Blimp1 knockout mice had a lower percentage of NK cells in peripheral lymphoid sites, such as spleen and peripheral blood, and higher percentage of NK cells in bone marrow when compared to wild-type mice. The maturation of NK cells was partially impaired in Blimp1 knockout mice. However, Blimp1-deficient NK cells proliferated better upon stimulation in vitro and in vivo, and had a potent cytotoxic ability. Together, these findings suggest potential pathways for therapeutic targeting in NKTCL patients.

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