title: Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias.
abstract: The c-myb proto-oncogene has been implicated in leukemogenesis, but possible mechanisms remain ill defined. To gain further insight to this process, we used transcript profiling in K562 cells expressing a dominant-negative Myb (MERT) protein. A total of 105 potential Myb gene targets were identified. Neuromedin U (NmU), a peptide affecting calcium transport, underwent the greatest expression change ( approximately 5-fold decrease). To verify a linkage between c-myb and NmU, their mRNA levels were quantitated using real-time polymerase chain reaction in primary acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as well as normal hematopoietic cells. We found that c-myb was elevated in AML and ALL samples, but NmU expression was increased only in AML cells. Significantly, only AML cells expressed the cognate receptor of NmU, NMU1R, suggesting the presence of a novel autocrine loop. We examined this possibility in detail. Exogenous NmU "rescued" growth suppression in K562-MERT cells and stimulated the growth of primary AML cells. Short interfering RNA "knockdown" of NmU in K562 cells arrested cell growth. Exposing Indo-1-labeled K562 cells to NmU induced an intracellular Ca(++) flux consistent with engagement of the NMU1R. Combined, these results suggest that NmU expression is related to Myb and that the NmU/NMU1R axis constitutes a previously unknown growth-promoting autocrine loop in myeloid leukemia cells.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Pennsylvania School of Medicine, 421 Curie Blvd, Philadelphia, PA 19104, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shetzline
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Rallapalli
authors.forename: Kelley J
authors.initials: KJ
authors.lastname: Dowd
authors.forename: Shaomin
authors.initials: S
authors.lastname: Zou
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakata
authors.forename: Cezary R
authors.initials: CR
authors.lastname: Swider
authors.forename: Anna
authors.initials: A
authors.lastname: Kalota
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Alan M
authors.initials: AM
authors.lastname: Gewirtz
mesh_terms: D019898:Autocrine Communication; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020570:Genes, myb / Q000235:genetics; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D006133:Growth Substances; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D009479:Neuropeptides; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D012337:RNA, Ribosomal, 18S; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; D013629:Tamoxifen; C056900:neuromedin U; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D002118:Calcium