Variant forms of alpha-fetoprotein transcripts expressed in human hematopoietic progenitors. Implications for their developmental potential towards endoderm

Hematopoietic stem cells have been identified as multipotent cells that give rise to all adult hematopoietic lineages. Although the hematopoietic lineage is derived from the mesodermal germ layer in the embryo, recent data suggest that bone marrow cells with an antigenic profile consistent with that of hematopoietic stem cells can also differentiate to cell types of the endodermal lineages, such as hepatocytes. However, the molecular mechanisms associated with these events are entirely unknown. For decades, alpha-fetoprotein (AFP) has been used as a differentiation marker for endodermal cells, because it was thought that the transcription of AFP mRNA is tightly regulated in a developmental and tissue-specific process. In this report we describe two new variant forms of AFP transcripts in human hematopoietic progenitors that are not expressed in mature cells. The variant AFP (vAFP) cDNA sequences isolated from a multipotent hematopoietic cell line, K562, revealed that the vAFP differed from the authentic transcript, consisting of 15 exons, by replacing exon 1 of AFP with one or two exons located in the 5'-untranslated region of the AFP gene. In addition to the K562 cell line, vAFP transcripts were detected in normal bone marrow, thymus, and brain but were not detected in normal spleen, intestine, liver, or the hepatocellular carcinoma cell line, HepG2. This suggests expression in normal hematopoietic progenitors. This hypothesis was confirmed by the finding that CD34(+)Lin(-) hematopoietic progenitor cells purified from cord blood by flow cytometric sorting also expressed the variant transcripts. These results suggest that some hematopoietic progenitors are in a state that permits them to express certain types of transcripts that have been considered unique to endoderm.