No abstract

Interferon consensus sequence binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Mice with a null mutation of ICSBP exhibit two prominent phenotypes related to previously described activities of the IRF family. The first is enhanced susceptibility to virus infections associated with impaired production of IFN(gamma). The second is deregulated hematopoiesis in both ICSBP-/- and ICSBP+/- mice that manifests as a syndrome similar to human chronic myelogenous leukemia. The chronic period of the disease progresses to a fatal blast crisis characterized by a clonal expansion of undifferentiated cells. Normal mice injected with cells from mice in blast crisis developed acute leukemia within 6 weeks of transfer. These results suggest a novel role for ICSBP in regulating the proliferation and differentiation of hematopoietic progenitor cells.

No abstract

Interleukin-2 (IL-2) is a lymphocytotropic hormone which is thought to have a key role in the immune response of mammalian cells. It is produced by a subpopulation of activated T-lymphocytes and acts in vitro as the principal auto- and paracrine T-cell growth factor (for reviews see refs 1-3). IL-2 is, however, not the sole T-cell growth factor, nor does it act exclusively on T cells, also promoting growth of NK cells and differentiation of B cells. A role for IL-2 in T-cell development has been postulated but remains controversial. Here we test the requirement for IL-2 in vivo using IL-2-deficient mice generated by targeted recombination. We find that mice homozygous for the IL-2 gene mutation are normal with regard to thymocyte and peripheral T-cell subset composition, but that a dysregulation of the immune system is manifested by reduced polyclonal in vitro T-cell responses and by dramatic changes in the isotype levels of serum immunoglobulins.

R115777 is a nonpeptidomimetic enzymespecific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (acti- vated IntroductionAdult acute leukemias remain formidable therapeutic challenge. Only 70% of adults with newly diagnosed acute myelogenous leukemias (AMLs) achieve complete remission (CR) after cytotoxic induction chemotherapy. Although these CRs may be prolonged in 35% to 40% of younger adults (age Ͻ 60), 1-5 the remainder have a relapse and die. Certain subgroups, including older adults, 3,5,6 patients with AMLs linked to environmental or occupational exposures (including therapy-induced AMLs), and patients with previous myelodysplasia (MDS) or other antecedent hematologic disorders, 7,8 have extremely poor outcomes, with CR rates of 40% or less, CR durations less than 12 months, and cure rates less than 10% to 15%. 3,5,6 The overall outlook for adult acute lymphoblastic leukemias (ALLs) is similar, 9-11 with a particularly poor prognosis in Philadelphia chromosome (Ph ϩ ) disease. 9,12 Thus, new approaches are needed to improve the outcome for adults with refractory leukemias.Improved understanding of signal transduction pathways has resulted in identification of a panoply of potential therapeutic targets. [13][14][15][16] Among these are the membrane-associated G proteins encoded by the ras family of proto-oncogenes. Ras proteins are activated downstream of protein tyrosine kinases (PTKs, eg, growth factor receptors) and, in turn, trigger a cascade of phosphorylation events through sequential activation of Raf, MEK-1, and ERKs (extracellular signal-related kinases). These events are critical to survival of hematopoietic cells. [16][17][18][19] The Ras proteins are synthesized as cytosolic precursors that must attach to the cell membrane to transmit signals. Membrane attachment depends on the addition of a 15-carbon farnesyl group to Ras, a reaction that is catalyzed by the enzyme farnesyltransferase (FT). [20][21][22] FT inhibitors (FTIs) were developed on the premise that FT inhibition would prevent Ras processing and, therefore, transduction of proliferative signals. [22][23][24] Subsequent studies, however, have suggested that the cytotoxic actions of FTIs might also involve other farnesylated ...

Adults and children with SNCL have a similar prognosis when treated with the same chemotherapy. EFS in high-risk patients has been markedly improved by including IVAC in protocol 89-C-41, and excellent results can be achieved with only four cycles of therapy. In protocol 89-C-41, GM-CSF was not beneficial.

Interleukin-2-deficient mice (IL-2-/-) crossed to a BALB/c genetic background develop a lymphoproliferative syndrome with severe hemolytic anemia and die within 5 weeks of age. The presence of autoantibodies of various specificities and inflammatory lesions in several organs are indicative of a generalized auto-immune disease. No alterations of the immune system were observed in 6-day-old animals, but 10-day-old mice already showed an increased proliferation and polyclonal activation of lymphocytes. The treatment of IL-2-/- mice with anti-gp39(CD40L) antibody prevented the disease and indicated that the appearance of activated CD4- T cells (CD44high, CD69-) represents the first alteration of the immune system in IL-2-/- mice. Collectively, our results suggest that an essential role of IL-2 in vivo, which is not compensated by other cytokines, is the maintenance of self tolerance.

Sialic acids are widely expressed as terminal carbohydrates on glycoconjugates of eukaryotic cells. Sialylation is crucial for a variety of cellular functions, such as cell adhesion or signal recognition, and regulates the biological stability of glycoproteins. The key enzyme of sialic acid biosynthesis is the bifunctional UDP-N-acetylglucosamine-2-epimerase͞N-acetylmannosamine kinase (UDP-GlcNAc 2-epimerase), which catalyzes the first two steps of sialic acid biosynthesis in the cytosol. We report that inactivation of the UDP-GlcNAc 2-epimerase by gene targeting causes early embryonic lethality in mice, thereby emphasizing the fundamental role of this bifunctional enzyme and sialylation during development. The need of UDP-GlcNAc 2-epimerase for a defined sialylation process is exemplified with the polysialylation of the neural cell adhesion molecule in embryonic stem cells.