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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1833-1840.
Prepublished online as a Blood First Edition Paper on June 8, 2004; DOI 10.1182/blood-2003-10-3577.
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Submitted October 20, 2003
Accepted May 8, 2004
Neuromedin U: A Myb regulated autocrine growth factor for human myeloid leukemias
Susan E Shetzline, Ravikumar Rallapalli, Kelley J Dowd, Shaomin Zou, Yuji Nakata, Cezary R Swider, Anna Kalota, John K Choi, and Alan M Gewirtz*
Division of Hematology/Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
* Corresponding author; email: gewirtz{at}mail.med.upenn.edu.
The c-myb proto-oncogene has been implicated in leukemogenesis, but possible mechanisms remain ill defined. To gain further insight to this process, we employed transcript profiling in K562 cells expressing a dominant negative Myb (MERT) protein. 105 potential Myb gene targets were identified. Neuromedin U (NmU), a peptide affecting calcium transport, underwent the greatest expression change (~5x decrease). To verify a linkage between c-myb and NmU, their mRNA levels were quantitated using real time PCR in primary acute myeloid (AML), and lymphoid (ALL) leukemias, as well as normal hematopoietic cells. c-Myb was elevated in AML and ALL samples, but NmU expression was increased only in AML cells. Significantly, only AML cells expressed NmU's cognate receptor, 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. siRNA "knockdown" of NmU in K562 cells arrested cell growth. Exposing Indo-1 labeled K562 cells to NmU induced an intracellular Ca+2 flux consistent with engagement of the NMU1R. Combined, these results suggest that NmU expression is Myb related, and that the NmU/NMU1R axis constitutes a previously unknown growth promoting autocrine loop in myeloid leukemia cells.
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