The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.

Cell surface expression of CD86 (mCD86) provides an important co-stimulatory signal which profoundly influences immune responses. In this report, we investigated the potential presence of a circulating soluble form of CD86 (sCD86) in normal individuals and patients with acute myeloid leukaemia (AML) or B cell chronic lymphocytic leukaemia (B-CLL). Circulating sCD86 was detected in the plasma of all normal individuals (1.04 ± 0.33 ng/ml, n = 51) and patients analysed. Plasma collected from AML patients in remission (n = 6) contained only low levels of sCD86 but significantly elevated levels (у2.65 ng/ml, P Ͻ 0.0001) were detected in 10/24 AML patients analysed at the time of presentation or relapse. Significantly elevated levels of sCD86 were also detected in 2/17 B-CLL patients. There was no correlation between sCD86 levels and other clinical parameters. RT-PCR analysis demonstrated that normal monocytes and dendritic cells, as well as isolated AML (n = 2) and B-CLL (n = 4) cells, expressed an alternatively spliced transcript of CD86 which encoded a soluble form absent in normal T, B and NK cells. The finding that a proportion of leukaemia patients contain elevated levels of sCD86 and that at least some leukaemic cells express sCD86 transcript suggests a potential role for sCD86 in modulating mCD86 signalling during the malignant process. Leukemia (2002) 16, 865-873.

Heparin is commonly used as an anticoagulant but its many other pharmacologic properties are less well known. It has an important effect on complement regulation and has been shown in vitro to inhibit complement-mediated lysis of red cells. Although the beneficial effects of heparin for treatment of haemolytic anaemia were described many decades ago, its use in this scenario is not standard practice. Here we report a case where the use of heparin had a beneficial effect on a life-threatening episode of intravascular haemolysis. We also show unfractionated heparin to be more beneficial than low molecular weight heparin. We suggest that heparin has an important role to play in the management of complement-mediated haemolytic episodes.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu) AML1/ETO and POU4F1 synergy drives B-lymphoid gene expression typical of t(8;21) acute myeloid leukemia Leukemia (2012Leukemia ( ) 26, 1131Leukemia ( --1135 doi:10.1038/leu.2011; published online 8 November 2011Cells of the acute myeloid leukemia (AML) t(8;21) subtype express the B-lymphoid lineage marker Paired Box 5 (PAX5), and frequently, but not always, express the characteristically B-lymphoid surface markers CD19 and CD79a. 1 --3 However, mechanisms for activation of this 'B-lineage' program and its potential contribution to the transformation process are unclear.Comprehensive studies of the t(8;21) translocation product AML1/ETO (also known as RUNX1/RUNX1T1 or AML1/MTG8) have identified its sufficiency in inhibition of myeloid gene function and immortalisation of both human and murine progenitors, however AML1/ETO alone is insufficient for leukemogenesis, suggesting it requires co-operating events to drive disease. 4 The POU homeobox gene POU4F1 (also known as BRN3A) is highly expressed in t(8;21) samples, with AML1/ETO appearing both to promote some BRN3A expression and co-operate with its protein product Brn3a to restrict myeloid gene expression. 5,6 An ability of Brn3a shRNA to impair AML1/ETO-dependent immortalisation of murine haematopoietic progenitor cells in vitro suggests an important role for BRN3A in the human disease. 6

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