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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 12 June 2008 (12.06.2008) WO 2008/070082 A2 (51) International Patent Classification: (74) Agents: CLAUSS, Isabelle, M. et al.; Patent Group, FO A6IK 48/00 (2006.01) LEY HOAG LLP, 155 Seaport Blvd., Boston, MA 02210- 2600 (US). (21) International Application Number: PCT/US2007/024845 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, 4 December 2007 (04.12.2007) CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (25) Filing Language: English IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, (26) Publication Language: English MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (30) Priority Data: PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, 60/872,764 4 December 2006 (04. 12.2006) US TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicants (for all designated States except US): THE JOHNS HOPKINS UNIVERSITY [US/US]; 3400 North (84) Designated States (unless otherwise indicated, for every Charles Street, Baltimore, MD 21218 (US). OHIO STATE kind of regional protection available): ARIPO (BW, GH, UNIVERSITY [US/US]; 1320 Kinnear Road, Columbus, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, OH 43212 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (75) Inventors/Applicants (for US only): GEORGANTAS, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, Robert [US/US]; 324 Stevenson Lane, Apt C2, Tow- GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). son, MD 21204 (US). CIVIN, Curt, I. [US/US]; 7516 LΗ irondelle Club Road, Towson, MD 21204-6417 (US). Published: CALIN, George, Adrian [US/US]; Columbus, OH (US). — without international search report and to be republished CROCE, Carlo, Maria [US/US]; Columbus, OH (US). upon receipt of that report (54) Title: STEM-PROGENITOR CELL SPECIFIC MICRO-RIBONUCLEIC ACIDS AND USES THEREOF (57) Abstract: Provided herein are methods and compositions for modulating the differentiation of incompletely differentiated cells, such as stem-progenitor cells, e.g., hematopoietic stem- progenitor cells. A method may comprise contacting a cell with an agononist or an antagonist of a miRNA comprising a nucleotide sequence from SEQ ID NO: 1-34. STEM-PROGENITOR CELL SPECIFIC MICRO-RIBONUCLEIC ACIDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 60/872,764, filed on December 4, 2006, the content of which is specifically incorporated by reference herein in its entirety. GOVERNMENTAL SUPPORT This invention was made with governmental support under grant numbers CA70970 and CA60441, awarded by the U.S. National Institutes of Health. The government has certain rights in this invention. BACKGROUND MicroRNAs (miRNAs) consist of a class of epigenetic elements that inhibit translation of mRNA to protein and also may result in gene silencing through chromatin remodeling (I). miRNAs have been identified in many organisms, including plants, Drosophila, rats, mice, and humans, where they have been shown to control major cellular processes, including metabolism, differentiation, and development (2). miRNAs have been implicated in the differentiation of mammalian blood cell lineages. miRNA-181 seems to bias mouse lymphoid progenitors toward B lymphoid development, and miRNA-146and - 223 bias toward T lymphopoiesis (3_). miRNA-221 and -222 are critically involved in the negative control of human erythropoiesis (4) and miRNA-223 in the down-regulation of mouse granulopoiesis (5). Given that miRNAs regulate normal cellular functions, it is not surprising that miRNAs also are involved in carcinogenesis. miRNAs have been identified at deleted or amplified genomic regions or translocation breakpoints in human cancers (6); e.g., miRNA-15 and -16 are the critical genetic elements deleted from 13ql4 chromosomal region in a subset ofchronic lymphocytic leukemia cases (7). SUMMARY OF THE INVENTION Provided herein are methods of modulating the differentiation or proliferation of an incompletely differentiated cell, e.g., a stem-progenitor cell, such as a hematopoietic cell. A method may comprise contacting a cell with a miRNA of one or more of SEQ ID NOS: 1 to 34 (Table 1). Contacting may comprise providing an miRNA to said cell, or providing an expression construct encoding said miRNA to said cell. The cell may be located in an animal subject, such as a human, or the cell may be contacted in vitro, wherein the method may comprise further culturing of said cell with or without reintroduction into an animal. In yet another embodiment, there is provided a method of modulating the proliferation or differentiation of a cell, e.g., a hematopoietic cell, comprising contacting said cell with an agent that is an antagonist of the function or expression of the miRNAs of SEQ ID NOS: 1-34 (Tables 1 and 6). The cell may be contacted in vitro, wherein the method may comprise further culturing of said cell, with or without reintroduction into an animal. The agent may be a peptide, protein, DNA, RNA, antisense DNA, antisense RNA or small molecule. In a further embodiment, there is provided a method of modulating differentiation of a cell, e.g., a hematopoietic cell, comprising inhibiting the function of one or more of the miRNAs of SEQ ID NOS: 1-34 (Tables 1 and 6). Inhibiting the function may comprise contacting the cell with one or more modified or unmodified antisense constructs directed to one or more of the miRNAs of SEQ ID NOS: 1-34. The cell may be located in an animal subject, such as a human, or the cell may be contacted in vitro, followed by culturing said cell in vitro, with or without reintroduction into an animal. In still a further embodiment, there is provided a method of modulating differentiation of a cell, e.g., a hematopoietic cell, comprising providing to said cell an agonist of one or more of the miRNAs of SEQ ID NOS: 1-34 (Tables 1 and 6). The agonist may be one or more of the miRNAs of SEQ ID NOS: 1-34. The agonist may also be an expression cassette encoding one or more of the miRNAs of SEQ ID NOS: 1-34. The agonist may be a peptide, protein, nucleic acid, or small molecule that stimulates the expression of one or more of the miRNAs of SEQ ID NOS: 1-34. The cell may be located in an animal subject, such as a human, or the cell may be contacted in vitro, and may be followed by culturing said cell in vitro, with or without reintroduction into the animal. Provided herein are method for modulating the differentiation of a cell, e.g., a stem- progenitor cell (SPC). A method may comprise contacting a stem-progenitor cell with one or more nucleic acids, wherein each nucleic acid comprises a nucleotide sequence that is at least about 90% identical to one or more of SEQ ID NOs: 1-34 or the complement thereof. Modulating the differentiation of a stem-progenitor cell may be inhibiting the differentiation of a stem-progenitor cell, in which case, the stem-progenitor cell is contacted with one or more nucleic acids, wherein each nucleic acid comprises a nucleotide sequence that is at least about 90% identical to one or more of SEQ ID NOs: 1-34. Modulating the differentiation of a stem-progenitor cell may be stimulating the differentiation of a stem- progenitor cell, in which case, the stem-progenitor cell is contacted with one or more nucleic acids, wherein each nucleic acid comprises a nucleotide sequence that is at least about 90% identical to one or more of the complements of SEQ ID NOs: 1-34. In one embodiment, the stem-progenitor cell is a hematopoietic stem-progenitor cell and the SEQ ID NOs are selected from the group consisting of the sequences of mir-128a, mir-181a, mir- 146, mir-155, mir-24a, mir-17, mir-16, mir-103, mir-107, mir-223, mir-221 and mir-222 or the complement thereof. The hematopoietic stem-progenitor cell may be a CD34+ cell. In one embodiment, the differentiation of a hematopoietic stem-progenitor cell beyond the stage of multipotent progenitor cell (MPP) and/or before the stage of common lymphoid progenitor (CLP) or common myeloid progenitor (CMP) is inhibited, and the SEQ ID NOs are selected from the group consisting of mir- 128a, mir-181a, mir-146, mir- 155, mir-24a, and mir-17. In one embodiment, the differentiation of a hematopoietic stem- progenitor cell beyond the stage of MPP andor before the stage of CLP is inhibited, and the SEQ ID NO is that of mir-146. In one embodiment, the differentiation of a hematopoietic stem-progenitor cell beyond the stage of MPP and/or before the stage of CMP is inhibited, and the SEQ ID NOs are selected from the group consisting of mir-155, mir-24a or mir-17. In one embodiment, the differentiation of a hematopoietic stem-progenitor cell beyond the stage of CMP and/or before the stage of B/Mac bi-potential is inhibited, and the SEQ ID NOs are those of mir-103 or mir-107.
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  • Therapeutic Evaluation of Micrornas by Molecular Imaging Thillai V

    Therapeutic Evaluation of Micrornas by Molecular Imaging Thillai V

    Theranostics 2013, Vol. 3, Issue 12 964 Ivyspring International Publisher Theranostics 2013; 3(12):964-985. doi: 10.7150/thno.4928 Review Therapeutic Evaluation of microRNAs by Molecular Imaging Thillai V. Sekar1, Ramkumar Kunga Mohanram1, 2, Kira Foygel1, and Ramasamy Paulmurugan1 1. Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA. 2. Current address: SRM Research Institute, SRM University, Kattankulathur– 603 203, Tamilnadu, India Corresponding author: Ramasamy Paulmurugan, Ph.D. Department of Radiology, Stanford University School of Medicine, 1501, South California Avenue, #2217, Palo Alto, CA 94304. Phone: 650-725-6097; Fax: 650-721-6921. Email: [email protected] © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2013.07.26; Accepted: 2013.09.22; Published: 2013.12.06 Abstract MicroRNAs (miRNAs) function as regulatory molecules of gene expression with multifaceted activities that exhibit direct or indirect oncogenic properties, which promote cell proliferation, differentiation, and the development of different types of cancers. Because of their extensive functional involvement in many cellular processes, under both normal and pathological conditions such as various cancers, this class of molecules holds particular interest for cancer research. MiRNAs possess the ability to act as tumor suppressors or oncogenes by regulating the expression of different apoptotic proteins, kinases, oncogenes, and other molecular mechanisms that can cause the onset of tumor development.