Mutations of the transcription factor PU.1 are not associated with acute lymphoblastic leukaemia

The transcription factor PU.1 plays a crucial role during normal haematopoiesis in both myeloid cells and B-lymphocytes. Mice with a disruption in both alleles of the PU.1 locus were found to lack macrophages and B cells and had delayed appearance of neutrophils. In addition, critical decrease of PU.1 expression is sufficient to cause acute myeloid leukaemia (AML) and lymphomas in mice. Recently, we reported that heterozygous mutations in the PU.1 gene are present in some patients with AML. Thus, we hypothesised that PU.1 mutations might also contribute to the development of acute leukaemias of the B-cell lineage. Here, we screened 62 patients with B-cell acute lymphoblastic leukaemia (B-ALL) at diagnosis for genomic mutations by direct sequencing of all five exons of the PU.1 gene. We found no genomic alteration of the PU.1 gene suggesting that PU.1 mutations are not likely to be common in B-ALL

Drug-mediated inhibition of Fli-1 for the treatment of leukemia

The Ets transcription factor, Fli-1 is activated in murine erythroleukemia and overexpressed in various human malignancies including Ewing's sarcoma, induced by the oncogenic fusion protein EWS/Fli-1. Recent studies by our group and others have demonstrated that Fli-1 plays a key role in tumorigenesis, and disrupting its oncogenic function may serve as a potential treatment option for malignancies associated with its overexpression. Herein, we describe the discovery of 30 anti-Fli-1 compounds, characterized into six functional groups. Treatment of murine and human leukemic cell lines with select compounds inhibits Fli-1 protein or mRNA expression, resulting in proliferation arrest and apoptosis. This anti-cancer effect was mediated, at least in part through direct inhibition of Fli-1 function, as anti-Fli-1 drug treatment inhibited Fli-1 DNA binding to target genes, such as SHIP-1 and gata-1, governing hematopoietic differentiation and proliferation. Furthermore, treatment with select Fli-1 inhibitors revealed a positive relationship between the loss of DNA-binding activity and Fli-1 phosphorylation. Accordingly, anti-Fli-1 drug treatment significantly inhibited leukemogenesis in a murine erythroleukemia model overexpressing Fli-1. This study demonstrates the ability of this drug-screening strategy to isolate effective anti-Fli-1 inhibitors and highlights their potential use for the treatment of malignancies overexpressing this oncogene

A Key Commitment Step in Erythropoiesis Is Synchronized with the Cell Cycle Clock through Mutual Inhibition between PU.1 and S-Phase Progression

During red blood cell development, differentiation and cell cycle progression are intimately and uniquely linked through interdependent mechanisms involving the erythroid transcriptional suppressor PU.1 and the cyclin-dependent kinase inhibitor p57KIP2

A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages

Dynamics-dependent density distribution in active suspensions

Self-propelled colloids constitute an important class of intrinsically non-equilibrium matter. Typically, such a particle moves ballistically at short times, but eventually changes its orientation, and displays random-walk behavior in the long-time limit. Theory predicts that if the velocity of non-interacting swimmers varies spatially in 1D, $v(x)$, then their density $\rho(x)$ satisfies $\rho(x) = \rho(0)v(0)/v(x)$, where $x = 0$ is an arbitrary reference point. Such a dependence of steady-state $\rho(x)$ on the particle dynamics, which was the qualitative basis of recent work demonstrating how to `paint' with bacteria, is forbidden in thermal equilibrium. We verify this prediction quantitatively by constructing bacteria that swim with an intensity-dependent speed when illuminated. A spatial light pattern therefore creates a speed profile, along which we find that, indeed, $\rho(x)v(x) = \mathrm{constant}$, provided that steady state is reached

On the meaning of effects of substrate structure on biological transport

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44802/1/10863_2005_Article_BF01516050.pd