Leukemia cells on diet : metabolic plasticity and new therapeutic strategies

Leukemia cells as many tumor cells are characterized by metabolic peculiarities. Historically, leukemia cells have been described as the prototypical glycolytic cells consuming high levels of glucose for producing energy. Here we have examined whether this quasi dogmatic perception was the best picture of leukemia cell metabolism at a time where drugs targeting a variety of metabolic pathways are emerging. In the first part of this work, we showed that glutamine is as critical as glucose to maintain leukemia cell proliferation but also that blocking glutamine metabolism in these cells could lead to a form of resistance. This adaptive mechanism was found to be glucose-independent but supported by the activation of the serine pathway. This discovery led us to document that silencing PHGDH (one of the enzyme of the serine pathway) and/or the use of serine-free diet could inhibit leukemia cell growth both in vitro and in vivo, an effect further increased when glutamine metabolism was blocked. In the second part of this work, we reasoned that since glucose also supports protein glycosylation, part of the growth inhibitory effects resulting from glucose deprivation (instead of merely resulting from the inhibition of glycolytic ATP production) could indirectly result from a defect in glycosylation of glutamine transporters. ASCT2, a major glutamine transporter, was indeed deglycosylated upon inhibition of glucose metabolism in leukemia cells. This work also unraveled the dispensability of ASCT2 to support leukemia cell growth but also identified upregulation of the neutral amino acid antiporter LAT1/SLC7A5 (ie, glutamine/leucine exchanger) as a mechanism counteracting the inhibition of glycosylation. In conclusion, our work brings important nuances in the understanding of leukemia cell metabolic determinants. Our data point in particular towards amino acids serine and leucine as key actors of leukemia cell metabolism that need to be handled to optimize the response to therapeutic modalities targeting glucose and glutamine metabolism.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201