**Acknowledgements**

*Acute Leukemias*

patient derived Ph+

**6. Conclusions**

ALL [119].

leukemic cell lines and patient samples [123].

second NADPH. Ru-5-P can then be converted into ribose-5-phosphate (R-5-P) by the enzymatic action of ribulose-5-phosphate isomerase. R-5-P can then be used in the synthesis of nucleotides. Alternatively, where redox homeostasis and not nucleotide synthesis is the major requirement of the cell Ru-5-P can be catalyzed by ribulose-5-phosphate epimerase, into xyulose-5-phosphate (X-5-P) and via a series of further metabolic reactions back into the glycolytic intermediates F-6-P and glyceraldehyde-3-phosphate. G-6-PD is the rate limiting step of the PPP and is regulated by the NADP+/NADPH ratio, RAS/PI3K signalling and phosphorylation by Src, whilst 6-PGD is inhibited by 3-PG [99]. In cancer, aberrant RAS signalling or activation of Src can promote activation of the PPP. In AML, a recent study showed upregulation of *G-6-PD* mRNA in approximately 60% of patients, although it was not correlated with overall survival or relapse [116]. Targeting of xenograft mice injected with the leukemic cell line K562, with the antimalarial drug dihydroartemisinin and the 6-PGD inhibitor Physicon resulted in decreased tumor growth, whilst primary leukemia cells isolated from the PB of AML patients showed significantly decreased viability, with no toxicity observed in hematopoietic cells isolated from healthy individuals [117]. A metabolomic study comparing primary AML samples with either high or low levels of ROS, have also shown increased levels of the PPP metabolites sedoheptulose-7-phosphate and Ru-5-P in the samples with higher ROS levels [16]. Another study, using both AML cell lines and patient material, showed increased glucose metabolism and increased flux through the PPP, alongside increased *G-6-PD* mRNA expression [118]. Importantly, this study showed that use of the G-6-PD inhibitor 6-aminonictoinamide (6-AN) in AML cell lines induced both *in vitro* and *in vivo* cytotoxicity, and induced apoptosis in primary AML cells but not normal HPCs. In B-ALL, redirection of carbon from the glycolytic pathway to the PPP by the serine/threonine-protein phosphatase 2A (PP2A), has been shown to occur to combat cellular oxidative stress. Synergistic inhibition of G-6-PD by 6-AN and PP2A inhibitor LB100 induced cell death in

Lipid metabolism has also been shown to be dysregulated in both solid tumors and hematological malignancies (reviewed in [120]). Increased fatty acid oxidation (FAO) allows cancer cells to overcome metabolic and oxidative stress through the generation of ATP and NADPH. Significant changes to lipid metabolite levels are seen in AML patient samples with either high levels or low levels of ROS [16], whilst suppression of NOX2 has also been shown to increase FAO [121]. Furthermore, inhibition of the FAO using Avocatin B results in decreased NADPH levels and ROS dependent cell death in primary human AML samples but not normal mononuclear cells [122]. In ALL, use of L-asparaginase has been shown to increase FAO activity as a metabolic escape mechanism, however use of the FAO inhibitor etomoxir in combination with L-asparaginase has been shown to increase sensitivity of both

In the last twenty years, it has become increasingly clear that ROS play a significant role in cellular signalling, particularly pathways associated with growth, differentiation and survival, whilst its roles in HSC quiescence and normal hematopoiesis have started to be delineated. In many cancers including hematological malignancies, ROS levels have been shown to be elevated, leading to aberrant signalling in these pathways. Previously, arguments for both the use of anti-oxidant and pro-oxidant treatments in leukemia have been made (reviewed in [124]). Despite the transformation of survival rates in patients with acute promyelocytic leukemia

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We are grateful to Blood Cancer UK for programmatic funding and to Tenovus Cancer Care for funding Andrew Robinson. We are grateful to Wellcome ISSF for funding aspects of ROS research. We are grateful for support from the NCRI AML trials cell bank and the AML patients for providing primary samples used in several of our studies.
