Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia

SMADs are evolutionarily conserved transducers of the differentiation and g rowth arrest signals from the transforming growth factor/BMP (TGF/BMP) fami ly of ligands, Upon receptor activation, the ligand-restricted SMADs(1-3,5) are phosphorylated in the C-terminal MH2 domain and recruit the common sub unit SMAD4/ DPC-4 gene to the nucleus to mediate target gene expression. Fr equent inactivating mutations of SMAD4, or less common somatic mutations of SMAD2 seen in solid tumors, suggest that these genes have a suppressor fun ction. How-ever, there have been no identified mutations of SMAD5, although the gene localizes to the critical region of loss in chromosome 5q31.1 (ch romosome 5, long arm, region 3, band 1, subband 1) in myelodysplasia (MDS) and acute myelogenous leukemia (AML). A ubiquitously expressed novel isofor m, SMAD5 beta, encodes a 351 amino acid protein with a truncated MH2 domain and a unique C-terminal tail of 18 amino acids, which may be the functiona l equivalent of inactivating mutations. The levels of SMAD5 beta transcript s are higher in the undifferentiated CD34(+) hematopoietic stem cells than in the terminally differentiated peripheral blood leukocytes, thereby impli cating the beta form in stem cell homeostasis. Yeast 2-hybrid interaction a ssays reveal the lack of physical interactions between SMAD5 beta and SMAD5 or SMAD4, The expression of SMAD5 beta may represent a novel mechanism to protect pluripotent stem cells and malignant cells from the growth inhibito ry and differentiation signals of BMPs. (C) 2000 by The American Society of Hematology.