LAUSR

Survival rates for children with acute lymphoblastic leukaemia (ALL) have improved considerably to over 90% in recent years but despite these advances, 15–20% of patients relapse. Current chemotherapeutic regimens are designed around the properties of bulk leukaemia cells, which differ from those of the leukaemia-initiating cell (LIC) populations (Cox et al, 2009). If drugs have no effect on LIC, these cells may proliferate and cause relapse. Given that several populations in childhood ALL have been shown to have LIC properties (Cox et al, 2009; Diamanti et al, 2013) the development of therapies that are effective against all leukaemia cells, with minimal toxicity to normal cells, is of utmost importance. Efforts to uncover the biological pathways that mediate drug resistance and promote cell survival have lead to the targeting of heat shock protein 90 (Hsp90). Hsp90 is a molecular chaperone protein involved in the maturation and stabilisation of a range of oncogenic client proteins, such as Bcr-Abl, Akt and IKK, that are known to be mutated and/or overexpressed in leukaemias (Mjahed et al, 2012). Targeting Hsp90 could have an impact on several oncogenic pathways and the use of Hsp90 inhibitors is a promising approach for cancer therapy (Hassane et al, 2008; Hertlein et al, 2010; Lancet et al, 2010; Hong et al, 2013). Alvespimycin (17-DMAG) targets the binding site of ATP in Hsp90 and has shown clinical activity in acute myeloid leukaemia (AML)(Lancet et al, 2010; Mjahed et al, 2012). Celastrol has been shown to increase tumour necrosis factorinduced apoptosis (Sethi et al, 2007) and disrupt the Hsp90/ Cdc37 complex (Zhang et al, 2008). Celastrol significantly impairs viability and engraftment of AML LIC by inhibiting nuclear factor-jB survival signals and inducing oxidative stress (Hassane et al, 2008). However, there are no reports on the efficacy of alvespimycin or celastrol in childhood ALL. The aim of this study was to examine the effects of these structurally and functionally distinct Hsp90 inhibitors (Hsp90i) on primary ALL cells and evaluate their potential when used in combination. Cells from 3 B-cell precursor (BCP)-ALL, 3 T-cell ALL (TALL) cases and 3 cord blood (CB) samples were incubated with alvespimycin for 24 h and celastrol for 48 h then compared for survival (Fig 1A). Clinical characteristics of ALL samples are shown in Table SI. The 50% inhibitory concentration (IC50) for alvespimycin was 10 2 nmol/l in