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Sukhai M.A.,Ontario Cancer Institute | Spagnuolo P.A.,Ontario Cancer Institute | Weir S.,University of Kansas Medical Center | Kasper J.,Leukemia & Lymphoma Society | And 2 more authors.
Blood | Year: 2011

Advancing novel therapeutic agents for the treatment of malignancy into the marketplace is an increasingly costly and lengthy process. As such, new strategies for drug discovery are needed. Drug repurposing represents an opportunity to rapidly advance new therapeutic strategies into clinical trials at a relatively low cost. Known on-patent or off-patent drugs with unrecognized anticancer activity can be rapidly advanced into clinical testing for this new indication by leveraging their known pharmacology, pharmacokinetics, and toxicology. Using this approach, academic groups can participate in the drug discovery field and smaller biotechnology companies can "de-risk" early-stage drug discovery projects. Here, several scientific approaches used to identify drug repurposing opportunities are highlighted, with a focus on hematologic malignancies. In addition, a discussion of the regulatory issues that are unique to drug repurposing and how they impact developing old drugs for new indications is included. Finally, the mechanisms to enhance drug repurposing through increased collaborations between academia, industry, and nonprofit charitable organizations are discussed. © 2011 by The American Society of Hematology.

Chan K.M.,Mayo Medical School | Zhang Z.,Mayo Medical School | Zhang Z.,Leukemia & Lymphoma Society
Journal of Biological Chemistry | Year: 2012

Lrwd1, a protein containing a leucine-rich repeat and aWD40 repeat domain, interacts with the origin replication complex (ORC), a protein complex involved in both initiation of DNA replication and heterochromatin silencing. Lrwd1 and ORC are known to co-purify with repressive histone marks (trimethylated lysine 9 of histone H3 (H3K9me3) and trimethylated lysine 20 of histone H4 (H4K20me3)) and localize to pericentric heterochromatin. However, how the Lrwd1 is recruited to heterochromatin and the functional significance of the localization of Lrwd1 to the heterochromatin are not known. Here, we show that Lrwd1 preferentially binds to trimethylated repressive histone marks in vitro, which is dependent on an intact WD40 domain but independent of ORC proteins. The localization of Lrwd1 and Orc2 at pericentric heterochromatin in mouse cells is lost in cells lacking H3K9me3 but not in cells lacking H4K20me3. In addition, depletion of HP1α has little impact on the localization of Lrwd1 on pericentric heterochromatin. Finally, depletion of Lrwd1 and Orc2 in mouse cells leads to increased transcription of major satellite repeats. These results indicate that the Lrwd1 is recruited to pericentric heterochromatin through binding to H3K9me3 and that the association of Lrwd1 with pericentric heterochromatin is required for heterochromatin silencing and maintenance. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Oliansky D.M.,Roswell Park Cancer Institute | Larson R.A.,University of Chicago | Weisdorf D.,University of Minnesota | Dillon H.,Leukemia & Lymphoma Society | And 4 more authors.
Biology of Blood and Marrow Transplantation | Year: 2012

Clinical research published since the first evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of acute lymphoblastic leukemia (ALL) in adults is presented and critically evaluated in this update. Treatment recommendations changed or modified based on new evidence include: (1) myeloablative allogeneic SCT is an appropriate treatment for adult (<35 years) ALL in first complete remission for all disease risk groups; and (2) reduced-intensity conditioning may produce similar outcomes to myeloablative regimens. Treatment recommendations unchanged or strengthened by new evidence include: (1) allogeneic SCT is recommended over chemotherapy for ALL in second complete remission or greater; (2) allogeneic is superior to autologous SCT; and (3) there are similar survival outcomes after related and unrelated allogeneic SCT. New treatment recommendations based on new evidence include: (1) in the absence of a suitable allogeneic donor, autologous SCT may be an appropriate therapy, but results in a high relapse rate; (2) it is appropriate to consider cord blood transplantation for patients with no HLA well-matched donor; and (3) imatinib therapy before and/or after SCT (for Ph+ ALL) yields significantly superior survival outcomes. Areas of needed research in the treatment of adult ALL with SCT were identified and presented in the review. © 2012 American Society for Blood and Marrow Transplantation.

Awad S.,United Arab Emirates University | Awad S.,University of Dundee | Ryan D.,University of Dundee | Prochasson P.,Stowers Institute for Medical Research | And 4 more authors.
Journal of Biological Chemistry | Year: 2010

The Saccharomyces cerevisiae Fun30 (Function unknown now 30) protein shares homology with an extended family of Snf2-related ATPases. Here we report the purification of Fun30 principally as a homodimer with a molecular mass of about 250 kDa. Biochemical characterization of this complex reveals that it has ATPase activity stimulated by both DNA and chromatin. Consistent with this, it also binds to both DNA and chromatin. The Fun30 complex also exhibits activity in ATP-dependent chromatin remodeling assays. Interestingly, its activity in histone dimer exchange is high relative to the ability to reposition nucleosomes. Fun30 also possesses a weakly conserved CUE motif suggesting that it may interact specifically with ubiquitinylated proteins. However, in vitro Fun30 was found to have no specificity in its interaction with ubiquitinylated histones. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Leukemia & Lymphoma Society | Date: 2014-08-01

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