Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells

To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient-derived CML CD34(+) cells, rendering them arginine auxotrophic. Thus, arginine deprivation completely blocks proliferation of CML CD34(+) cells and induces significantly higher levels of apoptosis when compared to arginine-deprived cell lines. Similarly, primary CML cells, but not normal CD34(+) samples, are particularly sensitive to treatment with the arginine-depleting enzyme, BCT-100, which induces apoptosis and reduces clonogenicity. Moreover, BCT-100 is highly efficacious in a patient-derived xenograft model, causing > 90% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs.

Automated summary

In order to fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which leads to specific nutrient dependencies. Arginine is identified as an essential nutrient for primary human CML cells through an amino acid drop-out screen and pre-clinical models. Deprivation of arginine completely blocks the proliferation of CML CD34(+) cells and induces higher levels of apoptosis compared to cell lines. Moreover, treatment with the arginine-depleting enzyme, BCT-100, is highly effective in reducing the number of human leukaemic stem cells (LSCs) in a patient-derived xenograft model.