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3.2.6 LSC Metabolism
Leukemia cells have two major metabolic challenges: how to meet the bioenergetic
and biosynthetic demands of increased cell proliferation and how to survive fluctua-
tions in external nutrient and oxygen availability in the BM environment. Some
studies have indicated a link between the microenvironment and leukemia cell
metabolism. The cholesterol-lowering drug lovastatin induces cell-autonomous
inhibition of LSCs in a co-culture system with MSCs but does not inhibit AML cells
cultured alone. Lovastatin pretreatment of LSC–stromal co-cultures also prolongs
survival of mice injected with these cells (Seton-Rogers 2013 ; Hartwell et al. 2013 ).
Adipocytes are the prevalent type of stromal cell in the adult BM, and fatty acids
produced by adipocytes modulate the activity of signaling molecules (Carracedo
et al. 2013 ; Behan et al. 2009 ). The finding that the rate of relapse after chemo-
therapy in mice injected with syngeneic leukemia cells was higher in obese mice
than in normal-weight mice (Behan et al. 2009 ) suggests the possibility that the
increased adipocyte content of adult BM promotes leukemia growth and negatively
affects sensitivity to chemotherapy. BM stromal cells promote survival of AML
cells via a metabolic shift from pyruvate oxidation to fatty acid β-oxidation (FAO),
which causes mitochondrial uncoupling that diminishes mitochondrial ROS forma-
tion and decreases intracellular oxidative stress linked to the Bcl-2 anti-apoptotic
machinery (Samudio et al. 2010 ). FAO is required for HSC self-renewal and quies-
cence (Ito et al. 2012 ). Another study demonstrated that AML stem cells rely on
oxidative phosphorylation and are unable to utilize glycolysis when mitochondrial
respiration is inhibited (Skrtić et al. 2011 ), showing that maintenance of mitochon-
drial function is essential for their survival (Lagadinou et al. 2013 ). These findings
suggest that acetyl-CoA produced by FAO fuels the Krebs cycle and oxidative phos-
phorylation. In turn, more recent evidence suggests that metabolic signals play criti-
cal roles determining transcriptional regulation; metabolic enzymes are often
present in transcriptional complexes, and thus provide a local supply of substrates/
cofactors (Suzuki et al. 2009 ). Interestingly, AML cells alter the immune microen-
vironment via release of high concentrations of arginase II, which suppresses T cell
proliferation, polarizes surrounding monocytes into a suppressive M2-like pheno-
type, and inhibits proliferation and differentiation of murine granulocyte-monocyte
progenitors and human CD34+ progenitors (Mussai et al. 2013 ). These findings sug-
gest that metabolic features supporting the AML BM niche may yield novel thera-
peutic targets.
3.2.7 A Commentary on Likely Future Directions
Circulating leukemia cells are effectively eliminated by traditional or targeted thera-
pies, whereas leukemia cells residing in the BM are chemoresistant and are respon-
sible for relapse. The BM microenvironment contributes to increase leukemic cell
Y. Tabe and M. Konopleva