Abstract 1124: Transcriptional control of B cell identity restricts metabolic fitness in human leukemia

Abstract

Abstract Oncogenic lesions in multi-potent progenitor cells often give rise to either B-cell or myeloid lineage leukemia. While transformed by the same oncogenes (e.g. BCR-ABL1, RAS), B-lineage and myeloid leukemias are distinct diseases. Given that oncogenic tyrosine kinase signaling (e.g. BCR-ABL1) imposes significant metabolic requirements on energy supply, biogenesis and metabolic fitness, we studied whether the divergent characteristics of myeloid and B-lineage leukemias have a metabolic basis. Metabolic analyses revealed that B-lineage acute lymphoblastic leukemia (Ph+ ALL) cells proliferate at maximum capacity of their glycolytic machinery. In contrast to myeloid leukemia (CML), B-lineage ALL cells lack metabolic adaptive fitness in response to metabolic fluctuations. C/EBPα-mediated reprogramming of B-lineage cells into the myeloid lineage induced glycolytic gene expression (Insr, Slc2a1, G6pdx, G6pd2, and Hk3). Frequent genetic lesions of transcription factors that determine B cell identity (IKZF1, PAX5, EBF1) partially mitigate B cell-instrinsic metabolic liability. Reconstitution of PAX5 expression in patient-derived B-lineage ALL cells reduced metabolic fitness by impacting glucose metabolism. Using genetic and metabolic experiments, we identified the metabolic liability observed in B-lineage ALL is in part dependent on the serine/threonine kinase LKB1. In agreement with previous studies, Cre-mediated deletion of Lkb1 induced proliferation in myeloid leukemia. Surprisingly, Lkb1 deletion led to apoptosis and decreased leukemogenic capacity in B-lineage leukemia. Consistent with the above observations, Arf, p53 and p27 levels were reduced in Lkb1-deficient myeloid leukemia cells, while Lkb1 deletion in B-lineage ALL cells up-regulated Arf, p53 and p27 levels. Enhanced glucose consumption and lactate production were observed in Lkb1-deficient myeloid leukemia cells. In contrast, loss of Lkb1 led to defective glycolytic and mitochondrial activity in B-lineage ALL. Lkb1 deletion in B-lineage ALL caused global accumulation of metabolites, suggesting that LKB1 is required for maintaining metabolic homeostasis. Moreover, loss of Lkb1 decreased protein levels of mitochondrial, anti-apoptotic BCL-2 family proteins, BCL-xL and MCL1, in B-lineage ALL. Reverse Phase Protein Array analyses revealed that LKB1 levels positively correlated with BCL-xL and MCL1 in patient-derived Ph+ ALL samples (n = 51) as well as other subtypes of B-lineage ALL (n = 183; MDACC, 1983-2007). Importantly, C/EBPα-mediated reprogramming of B-lineage ALL cells to the myeloid linage relieved dependency on LKB1. Taken together, we showed that transcriptional control of B cell identity causes unique metabolic liability. B-lineage ALL cells exhibit unique reliance on LKB1 for metabolic homeostasis and survival. Our findings revealed LKB1 as a potential therapeutic target in B-lineage ALL. Note: This abstract was not presented at the meeting. Citation Format: Lai N. Chan, Daniel Braas, Christian Hurtz, Seyedmehdi Shojaee, Huimin Geng, Valeria Cazzaniga, Carina Ng, Behzad Kharabi Masouleh, Yi Hua Qiu, Nianxiang Zhang, Kevin R. Coombes, Thomas Ernst, Giovanni Cazzaniga, Andreas Hochhaus, Steven Kornblau, Thomas Graeber. Transcriptional control of B cell identity restricts metabolic fitness in human leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1124. doi:10.1158/1538-7445.AM2015-1124