Expression of c-Fes protein isoforms correlates with differentiation in myeloid leukemias.
The cellular fes gene encodes a 93-kilodalton protein-tyrosine kinase (p93) that is expressed in both normal and neoplastic myeloid cells. Increased c-Fes expression is associated with differentiation in normal myeloid cells and cell lines. Our hypothesis was that primary leukemia cells would show a similar pattern of increased expression in more differentiated cells. Therefore, we compared c-Fes expression in cells with an undifferentiated, blast phenotype (acute myelogenous leukemia--AML) to cells with a differentiated phenotype (chronic myelogenous leukemia--CML). Instead of differences in p93 expression levels, we found complex patterns of c-Fes immunoreactive proteins that corresponded with differentiation in normal and leukemic myeloid cells. The "blast" pattern consisted of c-Fes immunoreactive proteins p93, p74, and p70; the "differentiated" pattern showed two additional c-Fes immunoreactive proteins, p67 and p62. Using mRNA from mouse and human cell lines, we found deletion of one or more exons in the c-fes mRNA. Those deletions predicted truncation of conserved domains (CDC15/FCH and SH2) involved in protein-protein interactions. No deletions were found, however, within the kinase domain. We infer that alternative splicing generates a family of c-Fes proteins. This may be a mechanism to direct the c-Fes kinase domain to different subcellular locations and/or substrates at specific stages of myeloid cell differentiation.
Carlson
Anne
A
Division of Hematology-Oncology, Department of Medicine and Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California, USA.
Berkowitz
Jeanne McAdara
JM
Browning
Damaris
D
Slamon
Dennis J
DJ
Gasson
Judith C
JC
Yates
Karen E
KE
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D019084:Fluorescent Antibody Technique, Indirect; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics; D020298:U937 Cells
D018952:Antigens, CD34; D020033:Protein Isoforms; D012333:RNA, Messenger