her chemotherapy drugs on in vivo production of Hsp90 by leukemia cells, Hsp90 is so highly abundant that we are tempted to speculate that Hsp90 production would not be affected by chemotherapy. Indeed, even though Hsp90 is known to be upregulated in response to cellular stress, major differences in protein levels are at best 23 fold only. In summary, we have validated Hsp90 as a soluble biomarker of ALL, for the earlier detection of leukemia engraftment and for monitoring leukemia kinetics, even at MRD levels and under chemotherapy treatment of mice. ~~ Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand is considered one of the most effective and reliable inducers of apoptosis in cancer cells. TRAIL, also known as APO-2 ligand and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19710468 TNFSF10, is a member of the Tumor Necrosis Factor family. TRAIL is a type II membrane protein, and, like TNF-, it can be cleaved from the membrane to produce a soluble, biologically active form. Expression of TRAIL transcripts has been detected in many human tissues, including spleen, lung, and prostate. TRAIL protein is encoded by the Apo2L gene located in chromosome 3. The gene spans 20 kb, contains five exons, and its expression is regulated by interferon – and IFN-. TRAIL forms homotrimers with a single Zn atom bound by the cysteine residue of each molecule in the GW 501516 trimeric ligand. Zinc stabilizes TRAIL homotrimer formation and is essential for its biological activity. TRAIL induces apoptosis utilizing components of both the extrinsic and the intrinsic apoptotic pathways. In the extrinsic pathway, apoptosis is initiated by interaction of TRAIL with PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19713490 its respective death receptors, DR4 and DR5. These interactions lead to trimerization of the receptor and clustering of the receptor intracellular death domains, followed by the formation of the death-inducing signaling complex. The DISC formation leads to the recruitment of the adaptor molecule FADD with subsequent binding and activation of the apical caspase-8 and -10. The activated caspase-8 and -10 then cleave and activate the `executioner’ caspase-3, -7, and -9. Activation of the `executioner’ caspases results in the cleavage of death substrates followed by cell death. TRAIL can also activate the intrinsic pathway by caspase-8-mediated cleavage of the proapoptotic Bid. Truncated Bid then interacts with proapoptotic Bax and Bak that cause the release in the cytosol of mitochondrial cytochrome c and SMAC/DIABLO. The existence of two TRAIL-mediated apoptotic pathways reveals the existence of two different cell types. In type I cells, the apoptotic pathway is independent of the intrinsic pathway and depends on the death receptor-mediated caspase-8 activation followed by the activation of effector caspases. In type II cells, apoptosis is dependent on the amplification of the apoptotic signal via the mitochondrial pathway. In many cancers, however, the normal apoptotic process is deregulated and the sensitivity to TRAIL is compromised. For example, downregulation of TRAIL death receptors DR4 and DR5, overexpression of negative regulators of apoptosis Bcl-2 or Bcl-X, and mutations in Bax, Bak, cFLIP, and caspase-8 have been reported to cause TRAIL resistance in various cancer cells. To overcome TRAIL resistance and to identify chemical compounds that can sensitize tumor cells to apoptosis we employed a high throughput screening approach followed by in silico modeling to expand chemical diversity of TRAIL-sensitizing compounds. In the present study we demonstr