Abstract 3547: B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 3547
• Main Authors: Vangapandu, Hima V., Havranek, Ondrej, Wierda, William G., Keating, Michael J., Davis, Richard Eric, Stellrecht, Christine M., Gandhi, Varsha
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-3547

Abstract Peripheral blood B cells in chronic lymphocytic leukemia (CLL) are quiescent, yet have an active RNA transcription and protein translation processes, suggesting that these malignant lymphocytes may be metabolically active. However, CLL metabolism and its relationship to disease biology has not been well-explored. In our previous investigation, we reported that compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in quiescent peripheral blood B lymphocytes from CLL patients (Vangapandu, H.V. et al, AACR 2014). In 45 patient samples tested, glycolysis (extracellular acidification rate, ECAR) was consistently low (1 to 15 mpH/min/5 x 105 lymphocytes), whereas, oxygen consumption rate (OCR) varied considerably (5 to 190 pMoles/min/5 x 105 lymphocytes). Among the prognostic factors, high OCR correlated strongly with ZAP 70 positivity, unmutated IGHV status, greater β2M levels and higher Rai stage. In contrast, glycolytic flux (ECAR) from same patient samples did not associate with prognostic factors. Further, OCR did not vary on the basis of frequently occurring cytogenetic abnormalities, 13q14, 17p, and 11q deletions or trisomy 12. Since, ZAP 70 and IGHV unmutated status are associated with augmented B-cell receptor (BCR) pathway signaling, we tested the impact on OCR after genetic ablation of B-cell receptor (CH2 region of IgM). A CRISPR-Cas9-mediated BCR knockout mitigated OCR in a malignant B cell line without impacting the rate of proliferation. A critical node in the BCR pathway is PI3 Kinase and PI3K isoforms, δ and γ are involved in B-cell malignancies. Consistent with BCR ablation results, knocking out PIK3CD (codes for catalytic subunit δ), dramatically reduced OCR and ECAR. Pharmacological inhibitors of the PI3K pathway, duvelisib (a PI3K δ/γ inhibitor in phase III clinical trials) or idelalisib (FDA approved PI3K δ inhibitor) also decreased OCR. Direct inhibition of AKT with MK-2206 showed similar results. Collectively, these data suggest that CLL cellular metabolism is associated with prognostic factors and linked to BCR signaling pathway. Since, the PI3K inhibitors used in our study are being tested clinically for patients with CLL, investigations on the impact on metabolomics during therapy and translation of results to combination strategies need to be explored. Note: This abstract was not presented at the meeting. Citation Format: Hima V. Vangapandu, Ondrej Havranek, William G. Wierda, Michael J. Keating, Richard Eric Davis, Christine M. Stellrecht, Varsha Gandhi. B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3547. doi:10.1158/1538-7445.AM2017-3547