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The Metabolic Profiles in Hematological Malignancies

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The Metabolic Profiles in Hematological Malignancies Indian J Hematol Blood Transfus (Oct-Dec 2019) 35(4):625–634 https://doi.org/10.1007/s12288-019-01107-8 REVIEW ARTICLE The Metabolic Profiles in Hematological Malignancies 1 1 2 Tao Liu • Xing-Chun Peng • Bin Li Received: 13 September 2018 / Accepted: 25 February 2019 / Published online: 23 April 2019 Ó Indian Society of Hematology and Blood Transfusion 2019 Abstract Leukemia is one of the most aggressive hema- Abbreviations tological malignancies. Leukemia stem cells account for AML Acute myeloid leukemia the poor prognosis and relapse of the disease. Decades of CML Chronic myeloid leukemia investigations have been performed to figure out how to T-ALL T-cell lymphoblastic leukemia eradicate the leukemia stem cells. It has also been known B-ALL B-cell lymphoblastic leukemia that cancer cells especially solid cancer cells use energy CLL Chronic lymphocytic leukemia differently than most of the cell types. The same thing MM Multiple myeloma happens to leukemia. Since there are metabolic differences MDS Myelodysplastic syndrome between the hematopoietic stem cells and their immediate LSCs Leukemia stem cells descendants, we aim at manipulating the energy sources OXPHOS Oxidative phosphorylation with which that could have an effect on leukemia stem FAO Fatty acid oxidation cells while sparing the normal blood cells. In this review PPP Pentose phosphate pathway we summarize the metabolic characteristics of distinct Glut1 Glucose transporter 1 leukemias such as acute myeloid leukemia, chronic mye- Ara-C Arabinofuranosyl cytidine loid leukemia, T cell lymphoblastic leukemia, B-cell 2-DG 2-Deoxy-D-glucose lymphoblastic leukemia, chronic lymphocytic leukemia RTKs Receptor tyrosine kinases and other leukemia associated hematological malignancies ROS Reactive oxygen species such as multiple myeloma and myelodysplastic syndrome. CSCs Cancer stem cells A better understanding of the metabolic profiles in distinct PPARc Proliferator-activated receptor gamma ligands leukemias might provide novel perspectives and shed light CPT1 Carnitine O-palmitoyltransferase I on novel metabolic targeting strategies towards the clinical GAT Gonadal adipose tissue treatment of leukemias. GA Glutaminase IDH1/2 Isocitrate dehydrogenase 1 and 2 Keywords Hematological malignancies Á Leukemia stem PHGDH Phosphoglycerate dehydrogenas cells Á Metabolism I-ASP l-Asparaginase GS Glutamine synthase ASNS Asparagine synthetase & Bin Li PRC2 Polycomb repressive complex 2 [email protected] 1 Department of Pathology, People’s Hospital of Longhua, Shenzhen 518131, People’s Republic of China 2 Department of Pathology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai Clinical Center, CAS, Huaihai Road 966, Shanghai City 200031, Shanghai, People’s Republic of China 123 626 Indian J Hematol Blood Transfus (Oct-Dec 2019) 35(4):625–634 Background discuss the metabolic profiles of four major leukemias as well as other hematological malignancies. In particular, we Leukemia is a kind of hematological malignancy that often underscore potential metabolic vulnerabilities for each type initiates in the bone marrow and leads to abnormal and of leukemia. immature white blood cells which are also named blasts or leukemia cells. In a contemporary view, LSCs is respon- sible for the initiation and development of the disease and Glucose Metabolism can explain most of the poor prognosis in clinical trials. Numerous studies have shed light on eliminating LSCs The well established Warburg effect has demonstrated that based on their distinct genetic and epigenetic characteris- solid cancer cells mainly use glycolysis to meet their tics compared with the normal blood stem cells [1, 2]. In energy requirement [10]. The Warburg effect had long recent decades, awareness that the metabolic phenotype of been believed to be an adaptation to low-oxygen environ- leukemia cells is heterogeneous and distinct from that of ment in cancer cells. Since most of the raw materials and their normal counterparts—is increasing. How the leuke- energy required for cell proliferation are from glycolysis, mia cells survive and propagate in adverse environment cancer cells need to activate glycolysis pathways although such as low glucose, hypoxia and oxidative stress remains they mostly reside in a condition that has enough oxygen. poorly understood [3, 4]. Targeting the glucose metabolism of leukemia cells has Glucose, free fatty acids, glutamine, amino acids are already becoming an emerging trend for leukemia basic and important materials for the catabolism pathways treatment. that support the growth and survival of the cancer cells. These catabolites are either assimilated from the blood Role in AML circulation or synthesized within cancer cells. Glucose is the among the most available nutrients in blood and a There are still some controversies concerning whether metabolic substrate generally utilized by cancer cells [5]. It AML cells use glycolytic metabolism or OXPHOS meta- is well known that anaerobic glycolysis and aerobic bolism although the glucose metabolism in AML has been mediated oxidative phosphorylation (OXPHOS) are the implicated in many studies. An interesting study by Wang two major pathways in glucose metabolism. Thus, various et al. had demonstrated that AML cells are so unique in the drugs that interfere with glycolysis and OXPHOS are being way they sense the glucose availability and utilization investigated and designed as anti-cancer agents. Fatty acids while normal cells do not get disrupted because they have are also essential substrates for catabolic pathways in other glucose metabolism in place in case of an emergency. cancers. The pentose phosphate pathway (PPP) mediated They suggested that by precise control of the level of glucose catabolism is known to be an important initiating glycolysis would be a novel therapeutical strategy for point for the production of NADPH and maintenance of a treating AML without affecting the normal function of the redox balance in normal cells [6]. However, fatty acid HSCs [11]. Besides, Saito et al. indicated that AMPK oxidation (FAO) take the place of PPP in cancer cells and deletion substantially delays leukemogenesis and eradi- contributes substantially to these processes under meta- cates LSCs in MLL-AF9 induced AML by downregulating bolic stress due to the low glucose levels [7]. Contrary to the expression of glucose transporter 1 (Glut1), enhancing the FAO catabolism, lipids and steroids are de novo syn- oxidative stress and inducing DNA damage. This study thesized to generate the new phospholipid bilayers, which powerfully supports that the Warburg effect does exist in are essential for the fast proliferation and division of the leukemia [12]. Moreover, Chen et al. [13] showed that cancer cells [8]. Glutamine is another indispensable nutri- elevated glycolysis decrease the vulnerability to anti-leu- ent for cancer cell growth since the amido nitrogen is an kemia agent arabinofuranosyl cytidine (Ara-C) while essential substrate for hexosamine and nucleotide synthesis inhibition of glycolysis suppresses AML cell growth and [9], and is also getting involved in TCA cycle to produce enhances cytotoxicity of Ara-C in killing leukemic cells. energy for cancer cells. Other critical metabolic processes Also, Larrue et al. demonstrated that the glycolytic inhi- include asparagine metabolism, folate metabolism and bitor 2-deoxy-D-glucose (2-DG) exhibited great anti-leu- oxidative stress metabolism. Like solid cancer cells, leu- kemia activity through modulating the expression of kemia cells are not metabolically homogenous and distinct receptor tyrosine kinases (RTKs) such as FLT-ITD and types of leukemia cells utilize special metabolic raw KIT. Modulating glycolysis by using 2-DG provides a material preferentially. Thus, targeting the metabolic dif- therapeutic approach in some subset of AML harboring ferences between leukemia cells and normal blood cells mutated RTKs [14]. One of the traditional ways of treating provides novel anti-leukemia strategy. In this review, we AML is by chemotherapy but sometimes it is not quite effective because of chemoresistance. A recent research by 123 Indian J Hematol Blood Transfus (Oct-Dec 2019) 35(4):625–634 627 Song et al. revealed that increased glycolysis and decreased metabolic regulators (mTORC1 and AMPK) could target OXPHOS may result in the drug resistance of AML cells. the CLL lymphocytes by reducing lactate production, thus Targeting anaerobic glycolysis metabolism is an effective decreasing aerobic glycolysis [19]. strategy for manipulating chemoresistance in AML [15]. Despite the numerous evidence proofing that AML mainly Role in CML uses glycolysis as their glucose utilization pathways, which is consistant with the solid cancer cells, an intriguing Glycolytic dependencies is also reported in CML. For investigation by Lagadinou et al. reported that OXPHOS is instance, Gottschalk et al. showed that imatinib (STI571), the unique fuel source for LSCs of AML. They discovered which is a classic inhibitor of the BCR-ABL oncoprotein, that LSCs in AML reside in a low levels of reactive oxygen induces cell apoptosis in human leukemia BCR-ABL species (termed ‘‘ROS-low’’) condition and exhibit a positive cells by altering the glucose metabolism from slower rate of energy metabolism compared with the nor- glycolysis to mitochondrial metabolism [20]. mal blood cells. Interestingly, they found that the anti- To sum up, leukemia cells may not always depend on apoptotic molecule BCL-2 is aberrantly
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