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CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells¹

Linda B. Baughn^*, Maurizio Di Liberto^*, Ruben Niesvizky, Hearn J. Cho^¶, David Jayabalan^*,, Joseph Lane, Fang Liu^|| and Selina Chen-Kiang^2,*,

^* Department of Pathology, Department of Medicine, and Department of Orthopaedics, Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, New York, NY 10065; ^¶ New York University Cancer Institute, Smilow Research Center 1304, New York, NY 10016; and ^|| Center for Advanced Biotechnology and Medicine and Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854

Resistance to growth suppression by TGF-β1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-β-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-β activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G₁ cyclin-dependent kinase (CDK) inhibitors (p15^INK4b, p21^CIP1/WAF1, p27^KIP1, p57^KIP2) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr⁸ (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-β resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-β resistance in multiple myeloma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a postdoctoral fellowship (L.B.B.) and Translational Research Program grants (S.C.-K. and M.D.L.) from the Leukemia and Lymphoma Society and National Institute of Health R01 grants CA93771 (F.L.) and CA120531 (S.C.-K.).

² Address correspondence and reprint requests to Dr. Selina Chen-Kiang, Department of Pathology, C-338, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065. E-mail address: sckiang{at}med.cornell.edu

³ Abbreviations used in this paper: CDK, cyclin-dependent kinase; BM, bone marrow; BMSC, bone marrow stromal cell; HMCL, human myeloma cell line; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; PCT, plasmacytoma; pS, phosphorylated serine; pSRb, phosphorylation of Rb on serine; pT8, phosphorylated Thr⁸.