Date of Graduation

5-2016

Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Varsha Gandhi, PhD

Committee Member

Peng Huang, MD, PhD

Committee Member

Gary Gallick, PhD

Committee Member

David McConkey, PhD

Committee Member

Zahid H. Siddik, PhD

Abstract

Metabolism of chronic lymphocytic leukemia (CLL), a disease characterized by the relentless accumulation of mature B cells has been little explored. Bone marrow stromal cells provide a survival benefit to CLL cells, in part through PI3K/AKT pathway. Compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in quiescent malignant B lymphocytes from CLL patients. Glycolysis (extracellular acidification rate, ECAR) was consistently low in CLL samples, but oxygen consumption (OCR) varied considerably. Higher OCR was associated with poor prognostic factors such as ZAP 70 positivity, unmutated IgVH, high β2M levels, and higher Rai stage. Co-culture with the NK-tert stromal line increased basal OCR and maximum respiratory capacity of CLL at 2 or 24 hours of interaction, without significant changes in glycolysis. Two other stromal lines displayed similar induction of OCR in CLL. The levels of ribonucleotide triphosphate pools in CLL cells were augmented with stromal interaction. PI3K inhibitors, duvelisib (IPI-145) and idelalisib (GS1101), and the AKT inhibitor MK-2206, dramatically reduced OCR, ECAR, and ribonucleotide pools in CLL cells. In concert, genetic ablation of PI3K in a malignant B cell line also diminished OCR and ECAR. Collectively, these data suggest that stroma affects metabolomics in quiescent CLL cells, driven in part by the PI3K/AKT pathway.

Keywords

OxPhos, CLL, stroma, leukemia, glycolysis, PI3K

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