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Creation of fusion genes by balanced chromosomal translocations is one of the hallmarks of acute myeloid leukemia (AML) and is considered one of the key leukemogenic events in this disease. In t(12;13)(p13;q12) AML,ectopic expression of the homeobox gene CDX2 was detected in addition to expression of the ETV6-CDX2 fusion gene,generated by the chromosomal translocation. Here we show in a murine model of t(12;13)(p13;q12) AML that myeloid leukemogenesis is induced by the ectopic expression of CDX2 and not by the ETV6-CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. The transforming capacity of Cdx2 depended on an intact homeodomain and the N-terminal transactivation domain. Transplantation of bone marrow cells expressing ETV6-CDX2 failed to induce leukemia. Furthermore,coexpression of ETV6-CDX2 and Cdx2 in bone marrow cells did not accelerate the course of disease in transplanted mice compared to Cdx2 alone. These data demonstrate that activation of a protooncogene by a balanced chromosomal translocation can be the pivotal leukemogenic event in AML,characterized by the expression of a leukemia-specific fusion gene. Furthermore,these findings link protooncogene activation to myeloid leukemogenesis,an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas. View Publication

We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant FGFR3 autophosphorylation by the small molecule inhibitor,PD173074. Inhibition of FGFR3 in human myeloma cell lines was associated with decreased viability and tumor cell growth arrest. Further,morphologic,phenotypic,and functional changes typical of plasma cell (PC) differentiation,including increase in light-chain secretion and expression of CD31,were observed and this was followed by apoptosis. Finally,using a mouse model of FGFR3 myeloma,we demonstrate a delay in tumor progression and prolonged survival of mice treated with PD173074. These results indicate that inhibition of FGFR3,even in advanced disease associated with multiple genetic changes,may allow the cell to complete its developmental program and render it sensitive to apoptotic signals. In addition,this represents the validation of a therapeutic target in MM that may benefit patients who have a very poor prognosis with currently available treatments. View Publication

Meis1 and Hoxa9 expression is upregulated by retroviral integration in murine myeloid leukemias and in human leukemias carrying MLL translocations. Both genes also cooperate to induce leukemia in a mouse leukemia acceleration assay,which can be explained,in part,by their physical interaction with each other as well as the PBX family of homeodomain proteins. Here we show that Meis1-deficient embryos have partially duplicated retinas and smaller lenses than normal. They also fail to produce megakaryocytes,display extensive hemorrhaging,and die by embryonic day 14.5. In addition,Meis1-deficient embryos lack well-formed capillaries,although larger blood vessels are normal. Definitive myeloerythroid lineages are present in the mutant embryos,but the total numbers of colony-forming cells are dramatically reduced. Mutant fetal liver cells also fail to radioprotect lethally irradiated animals and they compete poorly in repopulation assays even though they can repopulate all hematopoietic lineages. These and other studies showing that Meis1 is expressed at high levels in hematopoietic stem cells (HSCs) suggest that Meis1 may also be required for the proliferation/self-renewal of the HSC. View Publication

MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2,found in many human tumors,effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here,we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells,leading to cell cycle arrest,apoptosis,and growth inhibition of human tumor xenografts in nude mice. View Publication

Interleukin-6 (IL-6) is a critical factor in the regulation of stromal function and hematopoiesis. In vivo bromodeoxyuridine incorporation analysis indicates that the percentage of Lin(-)Sca-1(+) hematopoietic progenitors undergoing DNA synthesis is diminished in IL-6-deficient (IL-6(-/-)) bone marrow (BM) compared with wild-type BM. Reduced proliferation of IL-6(-/-) BM progenitors is also observed in IL-6(-/-) long-term BM cultures,which show defective hematopoietic support as measured by production of total cells,granulocyte macrophage-colony-forming units (CFU-GMs),and erythroid burst-forming units (BFU-Es). Seeding experiments of wild-type and IL-6(-/-) BM cells on irradiated wild-type or IL-6-deficient stroma indicate that the hematopoietic defect can be attributed to the stromal and not to the hematopoietic component. In IL-6(-/-) BM,stromal mesenchymal precursors,fibroblast CFUs (CFU-Fs),and stroma-initiating cells (SICs) are reduced to almost 50% of the wild-type BM value. Moreover,IL-6(-/-) stromata show increased CD34 and CD49e expression and reduced expression of the membrane antigens vascular cell adhesion molecule-1 (VCAM-1),Sca-1,CD49f,and Thy1. These data strongly suggest that IL-6 is an in vivo growth factor for mesenchymal precursors,which are in part implicated in the reduced longevity of the long-term repopulating stem cell compartment of IL-6(-/-) mice. View Publication

Gastropod mollusks have been used for over 2500 years to produce the Tyrian purple" dye made famous by the Phoenicians. This dye is constituted of mixed bromine-substituted indigo and indirubin isomers. Among these� View Publication

BACKGROUND Inhibition of bone resorption using bisphosphonates is an important step in palliation of complications of advanced cancer,such as hypercalcemia and metastatic bone disease. OBJECTIVE The goal of this article was to describe the pharmacologic properties of zoledronic acid (zoledronate) and discuss findings from preclinical and clinical studies of its use in skeletal disorders. METHODS Relevant English-language literature was identified using the terms zoledronic acid,zoledronate,Zometa,and 118072-93-8 through searches of MEDLINE (1966-June 2003) and International Pharmaceutical Abstracts (1970-June 2003),and abstract proceedings from the American Society of Clinical Oncology (1997-2002). RESULTS Zoledronic acid is a nitrogen-containing bisphosphonate that inhibits bone resorption. It is indicated for the treatment of hypercalcemia of malignancy and for the treatment of patients with multiple myeloma or documented metastasis from solid tumors,in conjunction with standard antineoplastic therapy. The recommended dosage is 4 mg via IV over textgreateror= 15 minutes every 3 or 4 weeks. Compared with pamidronate 90 mg,zoledronic acid 4 and 8 mg provided a higher complete response rate for hypercalcemia of malignancy by day 10 (88.4% and 86.7% vs 69.7%; P = 0.002 and P = 0.015) and longer duration of action (median time to relapse,30 and 40 days vs 17 days; P = 0.001 and P = 0.007). In patients with breast cancer or multiple myeloma,zoledronic acid was as effective as pamidronate in delaying time to a first skeletal-related event (373 days vs 363 days). In patients with hormone-refractory prostate cancer and bone metastases,zoledronic acid 4 mg reduced the proportion of patients who experienced a skeletal-related event (33% vs 44% with placebo; P = 0.021) or a skeletal fracture (13% vs 22% with placebo; P = 0.015). In patients with bone metastases from solid tumors,zoledronic acid delayed the median time to a first skeletal-related event (230 days vs 163 days with placebo; P = 0.023). Common adverse events include fever,nausea,constipation,fatigue,and bone pain. CONCLUSION Zoledronic acid is an effective and generally well-tolerated treatment for hypercalcemia of malignancy and skeletal complications of metastatic bone disease. View Publication

ARF GTPases are activated by guanine nucleotide exchange factors (GEFs) of the Sec7 family that promote the exchange of GDP for GTP. Brefeldin A (BFA) is a fungal metabolite that binds to the ARF1*GDP*Sec7 complex and blocks GEF activity at an early stage of the reaction,prior to guanine nucleotide release. The crystal structure of the ARF1*GDP*Sec7*BFA complex shows that BFA binds at the protein-protein interface to inhibit conformational changes in ARF1 required for Sec7 to dislodge the GDP molecule. Based on a comparative analysis of the inhibited complex,nucleotide-free ARF1*Sec7 and ARF1*GDP,we suggest that,in addition to forcing nucleotide release,the ARF1-Sec7 binding energy is used to open a cavity on ARF1 to facilitate the rearrangement of hydrophobic core residues between the GDP and GTP conformations. Thus,the Sec7 domain may act as a dual catalyst,facilitating both nucleotide release and conformational switching on ARF proteins. View Publication

Abnormal differentiation of myeloid cells is one of the hallmarks of cancer. However,the molecular mechanisms of this process remain elusive. In this study,we investigated the effect of tumor-derived factors on Janus kinase (Jak)/STAT signaling in myeloid cells during their differentiation into dendritic cells. Tumor cell conditioned medium induced activation of Jak2 and STAT3,which was associated with an accumulation of immature myeloid cells. Jak2/STAT3 activity was localized primarily in these myeloid cells,which prevented the differentiation of immature myeloid cells into mature dendritic cells. This differentiation was restored after removal of tumor-derived factors. Inhibition of STAT3 abrogated the negative effects of these factors on myeloid cell differentiation,and overexpression of STAT3 reproduced the effects of tumor-derived factors. Thus,this is a first demonstration that tumor-derived factors may affect myeloid cell differentiation in cancer via constitutive activation of Jak2/STAT3. View Publication

In this study,we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT),which converts lysophosphatidic acid to phosphatidic acid,on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176,CT-32458,and CT-32615 induced textgreater95% growth inhibition (P textless 0.01) in MM.1S,U266,and RPMI8226 MM cell lines,as well as MM cells from patients (IC(50),50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615,the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8,caspase-3,caspase-7,and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs),but not proteasome inhibitor PS-341,augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely,JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly,CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally,although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis,CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu,providing the framework for clinical trials of these novel agents in MM. View Publication

Recent findings have shown that embryonic vascular progenitor cells are capable of differentiating into mural and endothelial cells. However,the molecular mechanisms that regulate their differentiation,proliferation,and endothelial sheet formation remain to be elucidated. Here,we show that members of the transforming growth factor (TGF)-beta superfamily play important roles during differentiation of vascular progenitor cells derived from mouse embryonic stem cells (ESCs) and from 8.5-days postcoitum embryos. TGF-beta and activin inhibited proliferation and sheet formation of endothelial cells. Interestingly,SB-431542,a synthetic molecule that inhibits the kinases of receptors for TGF-beta and activin,facilitated proliferation and sheet formation of ESC-derived endothelial cells. Moreover,SB-431542 up-regulated the expression of claudin-5,an endothelial specific component of tight junctions. These results suggest that endogenous TGF-beta/activin signals play important roles in regulating vascular growth and permeability. View Publication

We have characterized several potential stem cell markers and defined the membrane properties of rat fetal (E10.5) neural stem cells (NSC) by immunocytochemistry,electrophysiology and microarray analysis. Immunocytochemical analysis demonstrates specificity of expression of Sox1,ABCG2/Bcrp1,and shows that nucleostemin labels both progenitor and stem cell populations. NSCs,like hematopoietic stem cells,express high levels of aldehyde dehydrogenase (ALDH) as assessed by Aldefluor labeling. Microarray analysis of 96 transporters and channels showed that Glucose transporter 1 (Glut1/Slc2a1) expression is unique to fetal NSCs or other differentiated cells. Electrophysiological examination showed that fetal NSCs respond to acetylcholine and its agonists,such as nicotine and muscarine. NSCs express low levels of tetrodotoxin (TTX) sensitive and insensitive sodium channels and calcium channels while expressing at least three kinds of potassium channels. We find that gap junction communication is mediated by connexin (Cx)43 and Cx45,and is essential for NSC survival and proliferation. Overall,our results show that fetal NSCs exhibit a unique signature that can be used to determine their location and assess their ability to respond to their environment. View Publication