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Molecular and Cellular Biology, April 2007, p. 3056-3064, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01339-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Rbm15 Modulates Notch-Induced Transcriptional Activation and Affects Myeloid Differentiation{triangledown} ,{dagger}

Xianyong Ma,1,{ddagger} Matthew J. Renda,1,{ddagger} Lin Wang,1 Ee-chun Cheng,1 Chao Niu,2 Stephan W. Morris,2 Andrew S. Chi,1 and Diane S. Krause1*

Departments of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, Connecticut,1 Departments of Pathology and Tumor Cell Biology at St. Jude Children's Research Hospital and Department of Pediatrics, University of Tennessee, College of Medicine, Memphis, Tennessee2

Received 20 July 2006/ Returned for modification 12 September 2006/ Accepted 22 January 2007

RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leukemia. To understand the role of the RBM15-MKL1 fusion protein in leukemia, we must understand the normal functions of RBM15 and MKL. Here, we show a role for Rbm15 in myelopoiesis. Rbm15 is expressed at highest levels in hematopoietic stem cells and at more moderate levels during myelopoiesis of murine cell lines and primary murine cells. Decreasing Rbm15 levels with RNA interference enhances differentiation of the 32DWT18 myeloid precursor cell line. Conversely, enforced expression of Rbm15 inhibits 32DWT18 differentiation. We show that Rbm15 alters Notch-induced HES1 promoter activity in a cell type-specific manner. Rbm15 inhibits Notch-induced HES1 transcription in nonhematopoietic cells but stimulates this activity in hematopoietic cell lines, including 32DWT18 and human erythroleukemia cells. Moreover, the N terminus of Rbm15 coimmunoprecipitates with RBPJ{kappa}, a critical factor in Notch signaling, and the Rbm15 N terminus has a dominant negative effect, impairing activation of HES1 promoter activity by full-length-Rbm15. Thus, Rbm15 is differentially expressed during hematopoiesis and may act to inhibit myeloid differentiation in hematopoietic cells via a mechanism that is mediated by stimulation of Notch signaling via RBPJ{kappa}.

* Corresponding author. Mailing address: Yale University School of Medicine, Department of Laboratory Medicine, P.O. Box 208035, 333 Cedar Street, New Haven, CT 06520-8035. Phone: (203) 688-4829. Fax: (203) 688-2748. E-mail: diane.krause{at}yale.edu

{triangledown} Published ahead of print on 5 February 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to the work.

Molecular and Cellular Biology, April 2007, p. 3056-3064, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01339-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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