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Compelling preclinical evidence  of BET inhibitors antileukaemic activity both in B- and [http://www.selleckchem.com/products/Romidepsin-FK228.html Selleck FK228] T-cell ALL has also emerged from a number of studies. In B ALL, a clear antiproliferative and pro-apoptotic effect was seen with JQ1 treatment in vitro and in xenotransplantation models. Along with MYC, an equally strong depletion of interleukin 7 receptor gene (IL7R) transcripts was observed, confirmed by reduced IL7R surface expression. IL7R expression is restricted to early lymphoid lineage cells and plays an important role in normal development and leukaemogenesis [Ott et al. 2012]. JQ1 downregulates MYC and induces cell cycle arrest and apoptosis in T lymphoblastic cell lines and primary cells, including treatment-refractory paediatric T-ALL, both in vitro and in NSG transplanted mice. JQ1 is effective regardless of the underlying oncogenic events, including Notch-driven ALL, refractory to Notch inhibitors [Roderick et al. 2014]. The latter was linked to a distal Notch1 enhancer which ordinarily interacts with the Myc proximal promoter. However, in Notch inhibitor-refractory cells, Myc transcription is driven by an alternative, Brd4-dependent promoter, hence the sensitivity of these cells to Brd4 inhibition. This is an interesting example of overcoming drug resistance  with BET protein inhibitors and provides the rationale for combination therapies in T ALL [Yashiro-Ohtani et al. 2014]. I-BET762, OTX015 and CPI-0610 are currently being evaluated in phase I clinical trials (Table 1). Preliminary results have been reported from the OTX015 trial in refractory haematological malignancies. A total of four of 14 patients with relapsed/refractory secondary or therapy-related AML receiving OTX015 at either 80 mg once daily or 40 mg twice daily had measurable responses, including one complete remission (CR) and one CR with incomplete blood count recovery [Herait et al. 2013]. This is the first published evidence of clinical activity for a BET protein  inhibitor in patients with advanced haematological malignancy. Multiple myeloma The preclinical evidence of antimyeloma activity of BET protein inhibition was first demonstrated with JQ1 treatment of myeloma cell lines, in xenograft myeloma models and the Vk*MYC transgenic mice. JQ1 induces cell proliferation arrest in myeloma cell lines (IC-50 68�C502?nM) and pronounced cell senescence, even in the presence of HS-5 stromal cells. A similar effect was seen in CD138+ primary cells from patients with relapsed/refractory myeloma. The in vivo therapeutic potential of JQ1 was tested in an orthotopic mouse xenograft model using MM1.S-luc cells. The animals were given daily intraperitoneal JQ1 injections, resulting in significant reduction of myeloma tumour burden and prolonged survival.