MicroRNA Fingerprints During Human Megakaryocytopoiesis
Described herein are compositions and methods of decreasing expression of MAFB in a subject having a cancer and/or myeloproliferative disorder associated with overexpression of a MAFB gene product where an effective amount of at least one miR-130a gene product or an isolated variant or biologically-active fragment thereof is administered to the subject sufficient to decrease expression of the MAFB gene product in the subject.
1 . A pharmaceutical composition for treating a subject having a cancer and/or a myeloproliferative disorder associated with overexpression of a transcription factor gene product from the Maf family, also known as protooncogene c-Maf or V-maf musculoaponeurotic fibrosarcoma oncogene homolog, (MAFB) gene product,
wherein the cancer and/or myeloproliferative disorder is selected from the group consisting of: acute myeloid leukemia (AML), acute megakaryoblastic leukemia (AMKL), multiple myeloma (MM), and chronic myelogenous leukemia (CML),
the composition comprising an effective amount of at least one miR-130a gene product and a pharmaceutically-acceptable carrier, wherein the at least one miR-130a gene product binds to, and decreases expression of, the MAFB gene product in the subject.
2 . The pharmaceutical composition of claim 1 , wherein the at least one miR-130a gene product comprises a nucleotide sequence that is complementary to a nucleotide sequence in the MAFB gene product.
3 . The pharmaceutical composition of claim 1 , wherein the at least one miR-130a gene product comprises a nucleotide sequence that is complementary to at least five nucleotides of the 3′ untranslated region (UTR) of MAFB.
4 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition further comprises at least one anti-cancer agent.
5 . The pharmaceutical composition of claim 4 , wherein the at least one anti-cancer agent is selected from the group consisting of: cytidine arabinoside, methotrexate, vincristine, etoposide (VP-16), doxorubicin (adriamycin), cisplatin (CDDP), dexamethasone, arglabin, cyclophosphamide, sarcolysin, methylnitrosourea, fluorouracil, 5-fluorouracil (5FU), vinblastine, camptothecin, actinomycin-D, mitomycin C, hydrogen peroxide, oxaliplatin, irinotecan, topotecan, leucovorin, carmustine, streptozocin, CPT-11, taxol, tamoxifen, dacarbazine, rituximab, daunorubicin, 1-β-D-arabinofuranosylcytosine, imatinib, fludarabine, docetaxel, and FOLFOX4.
6 . The pharmaceutical composition of claim 1 , wherein the subject has been diagnosed with acute myeloid leukemia (AML).
7 . The pharmaceutical composition of claim 1 , wherein the at least one miR-130a gene product consists of a sequence having at least 90% identity to SEQ ID:136 and/or SEQ ID:383.
8 . The pharmaceutical composition of claim 1 , wherein the at least one miR-130a gene product comprises a sequence having at least 95% identity to SEQ ID:136 and/or SEQ ID:383.
9 . The pharmaceutical composition of claim 1 , wherein the wherein the at least one miR-130a gene product comprises one or more chemical modifications selected from the group consisting of: sugar modifications, backbone modifications, and combinations thereof.
10 . The pharmaceutical composition of claim 1 , wherein the wherein the at least one miR-130a gene product is produced recombinantly.
11 . An artificial agonist of miR-130a, wherein the agonist is a polynucleotide comprising a pri-miRNA, pre-miRNA, or mature sequence of miR-130a, and wherein administration of the agonist decreases expression of a MAFB gene product in at least one cell following administration of the agonist.
12 . A pharmaceutical composition for treating a subject diagnosed with AML comprising the agonist of claim 11 in a pharmaceutically-acceptable carrier.
13 . The pharmaceutical composition of claim 12 , wherein the polynucleotide is encapsulated by liposomes.
14 . The agonist of claim 11 , wherein the polynucleotide is about 18 to about 25 nucleotides in length.
15 . The agonist of claim 11 , wherein the polynucleotide is double-stranded.
16 . The agonist of claim 11 , wherein the polynucleotide comprises a sequence of SEQ ID NO: 136 or SEQ ID NO: 383.
17 . The agonist of claim 11 , wherein the polynucleotide is encoded by an expression vector.
18 . The agonist of claim 11 , wherein the polynucleotide is nuclease resistant.