AbstractRhabdomyosarcoma is a childhood tumor of the skeletal muscle lineage in which cells display defects in both biochemical and morphological aspects of differentiation. The immunoglobulin superfamily members CDO and BOC are components of a cell surface receptor that positively regulates myogenesis in vitro. Expression of Cdo and Boc in myoblast cell lines is downregulated by the ras oncogene, and forced re‐expression of either Cdo or Boc can override ras‐induced inhibition of myogenic differentiation [Kang et al., J Cell Biol 1998; 143:403–413; Kang et al., EMBO J 2002; 21:114–124]. The current study sought to test whether the promyogenic properties of CDO and BOC could be extended to a human rhabdomyosarcoma cell line, RD. Stable overexpression of CDO or BOC in RD cells led to enhanced expression of two markers of muscle cell differentiation, troponin T and myosin heavy chain, and to increased formation of elongated, myosin heavy chain–positive myotubes. These observations are consistent with the notion that CDO and BOC play a role in the inverse relationship between differentiation and transformation of cells in the skeletal muscle lineage. © 2003 Wiley‐Liss, Inc.