Ikaros is a transcription factor that acts both as an activator and as an inhibitor of gene expression in several hematopoietic lineages. Ikaros functions in hematopoiesis have mostly been studied in mice, and are notably crucial for lymphopoiesis. Deregulation of Ikaros expression was evidenced in several leukemia subtypes, including pre-B-ALL. Here, we studied the role of Ikaros in human B lymphoid differentiation through xeno-transplantation of genetically modified cord blood (CB) human hematopoietic progenitor cells (HPC) in NOD/SCID mice. We used lentiviral vectors to force expression of Ikaros 6 (Ik6), a known dominant negative (DN) protein that interferes with normal Ikaros and structurally related proteins in HPC and their progeny. Two types of vectors were used: a vector containing the EF1alpha promoter which produces strong gene expression in all hematopoietic lineages, and a recently validated B-specific vector containing an enhanced CD19 derived promoter that strongly favors expression in the B-cell lineage. Ik6 transduction of CB CD34(+) cells with these vectors produced distinct consequences in the B-cell differentiation profiles of xenografted human cells. While the ubiquitous vector favored a specific block at the early pro-B/pre-B stage of differentiation, with an increase in Lambda Like transcript expression in the bone marrow (BM), B-specific Ik6 expression provoked a global decrease in the CD19(+) cell population in both BM and spleen, associated with a decrease in IgM+ immature B-cells in the spleen. We conclude that Ikaros proteins are active throughout human B-cell differentiation, before and after CD19 appearance.
"The deletions either involve the entire IKZF1 locus, resulting in loss of function, or delete an internal subset of IKZF1 exons, resulting in the expression of dominant negative IKZF1 alleles. Expression of such dominant negative IKZF1 alleles in hematopoietic progenitors impairs lymphoid development , and loss of IKZF1 accelerates the onset of Ph+ ALL in a retroviral bone marrow transplant and transgenic models of this disease . Several studies demonstrated that IKZF1 deletions are significantly associated with an increased relapse rate and adverse events and are correlated with poor outcome in patients with Ph+ ALL [27–29]. "
[Show abstract][Hide abstract] ABSTRACT: During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T-acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles.
[Show abstract][Hide abstract] ABSTRACT: The paper first addresses what is known and used, then it discusses what is known but not yetused. The third topic is what is not yet known or understood. Machines and their constituent elements are everywhere in modern society, ranging from the largest aircraft and ships to micropumps and gears. Everywhere machine elements exist, so too do tribological problems present themselves. Occasionally, the designers' understanding of tribology is sufficient to provide an adequate solution to a design requirement, but this is not the usual case. More typically, the designer is unaware of valuable tribological research, or else the research base is inadequate. Using this classification scheme, machine elements are discussed according to whether or not the designer's background is adequate, where it lags behind the tribology research community, and where existing research provides no great assistance to designers and impedes product development.
Lautaro D Álvarez, M Virginia Dansey, Diego Y Grinman, Daniela Navalesi, Gisela A Samaja, M Celeste Del Fueyo, Niek Bastiaensen, René Houtman, Darío A Estrin, Adriana S Veleiro, Adali Pecci, Gerardo Burton
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