Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Although promising new therapies for this incurable disease are being tested in clinical trials, the therapeutic relevance of metabolic rewiring in chronic lymphocytic leukemia (CLL) is poorly understood. The aim of this study was to identify targetable metabolic differences in primary CLL lymphocytes by the use of Dasatinib. Dasatinib is a multi-tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and is being tested in clinical trials for several cancers including CLL. This drug has been shown to be beneficial to CML patients suffering from diabetes by reducing their glucose plasma levels. In keeping with this previous observation, we report that Dasatinib induced glucose use while reducing lactate production, suggesting that this tyrosine kinase inhibitor decreases aerobic glycolysis and shifts glucose use in primary CLL lymphocytes. Our results suggest that primary CLL lymphocytes (independently of traditional prognostic factors) can be stratified in two subsets by their sensitivity to Dasatinib in vitro. Increased glucose use induced by Dasatinib or by inhibition of mitochondrial respiration was not sufficient to sustain survival and ATP levels in CLL samples sensitive to Dasatinib. The two subsets of primary CLL lymphocytes are characterized as well by a differential dependency on mitochondrial respiration and the use of anabolic or catabolic processes to cope with induced metabolic/energetic stress. Differential metabolic reprogramming between subsets is supported by the contrasting effect on the survival of Dasatinib treated CLL lymphocytes with pharmacological inhibition of two master metabolic regulators (mTorc1 and AMPK) as well as induced autophagy. Alternative metabolic organization between subsets is further supported by the differential basal expression (freshly purified lymphocytes) of active AMPK, regulators of glucose metabolism and modulators of AKT signaling. The contrasting metabolic features revealed by our strategy could be used to metabolically target CLL lymphocyte subsets creating new therapeutic windows for this disease for mTORC1 or AMPK inhibitors. Indeed, we report that Metformin, a drug used to treat diabetes was selectively cytotoxic to Dasatinib sensitive samples. Ultimately, we suggest that a similar strategy could be applied to other cancer types by using Dasatinib and/or relevant tyrosine kinase inhibitors.
Highlights
Chronic lymphocytic leukemia (CLL), the most common adult B cell malignancy in the western world, is characterized by the accumulation of monoclonal peripheral CD5+ B cells in the blood and in primary and secondary lymphoid tissues of affected patients
We tested the effect of a non toxic concentration of another inhibitor of OXPHOS, 200nM Rotenone which is a specific inhibitor of mitochondrial complex I [26] and resulted in a significant and similar increase in lactate production and glucose use as the one obtained by Oligomycin confirming the bioenergetic www.impactjournals.com/oncotarget organization of CLL lymphocytes without differences between subsets
Our results suggests that the differences in basal AMPK and ULK phosphorylation between subsets are intrinsic to the samples since there was no change on their expression by co-culturing primary CLL lymphocytes with stromal cells (BMS2 cells) previously reported to increase primary CLL lymphocyte survival by up-regulating survival pathways and affecting the metabolisms of these leukemic cells [37] (Supplementary FIGURE 1CD)
Summary
Chronic lymphocytic leukemia (CLL), the most common adult B cell malignancy in the western world, is characterized by the accumulation of monoclonal peripheral (mature) CD5+ B cells in the blood and in primary and secondary lymphoid tissues of affected patients. Prolonged survival of CLL lymphocytes has been associated with increased ligand-independent signaling activation downstream of the B-cell receptor This has led to the clinical testing of non-receptor tyrosine kinase inhibitors that target key Src family kinases (i.e. Dasatinib), BTK family kinase inhibitors (i.e. Ibrutinib) and PI3K inhibitors (i.e. CAL-101) [2,3,4]. It has been suggested that cancer cell metabolism is adapted to support high rates of proliferation and growth These metabolic changes include higher rates of aerobic glycolysis (Warburg effect) and lipid metabolisms [8,9,10]. Our results demonstrate that Dasatinib-induces energetic stress in primary CLL lymphocytes in vitro and that AMPK activation contributes to Dasatinib-drug resistance in a subset of primary CLL samples independently of traditional prognostic factors
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