Mucin1 expression is enriched in the human stem cell fraction of cord blood and is upregulated in majority of the AML cases.
OBJECTIVE
Mucin1 is a membrane glycoprotein that is overexpressed in a variety of human cancers. Here, we analyzed the role of Mucin1 in human hematopoietic stem/progenitor cells as well as in acute myeloid leukemia (AML) cells.


METHODS
Mucin1 expression was determined within the normal stem cell and progenitor compartment, as well as in the AML CD34+ and CD34- subfractions of patient samples. Stem cells were enumerated in long-term culture-initiating cell (LTC-IC) assays in limiting dilution and progenitor frequencies in colony-forming cell (CFC) assays in methylcellulose, and consequences of elevated Mucin1 expression were studied using retroviral overexpression systems in cord blood (CB) CD34+ cells.


RESULTS
Ten percent of CB and 5% of peripheral blood CD34+ cells expressed Mucin1. Retroviral overexpression of Mucin1 in CB CD34+ cells resulted in elevated stem cell and progenitor frequencies as determined in LTC-IC and CFC assays without affecting differentiation, which coincided with increased proliferation. Overexpression of intercellular adhesion molecule-1, a ligand for Mucin1, in MS5 stromal cells further increased LTC-IC frequencies. Mucin1 overexpression was associated with increased nuclear factor-kappaB p50 nuclear translocation, suggesting that Mucin1-induced phenotypes involve increased cell survival mechanisms. Finally, we observed increased Mucin1 expression in 70% of the AML cases (n=24), suggesting that elevated Mucin1 levels might be involved in regulating the proliferative potential of the immature leukemic compartment as well.


CONCLUSIONS
Our data indicate that hematopoietic stem cells as well as CD34+ AML subfractions are enriched for Mucin1 expression, and that overexpression of Mucin1 in CB cells is sufficient to increase both progenitor and LTC-IC frequencies.
Fatrai
Szabolcs
S
Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
Schepers
Hein
H
Tadema
Henko
H
Vellenga
Edo
E
Daenen
Simon M G J
SM
Schuringa
Jan Jacob
JJ
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D005312:Fetal Blood / Q000502:physiology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007231:Infant, Newborn; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D018396:Mucin-1 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000502:physiology*; D015854:Up-Regulation
D015703:Antigens, CD; D018952:Antigens, CD34; D017931:DNA Primers; C060192:MUC1 protein, human; D018396:Mucin-1; D018799:Intercellular Adhesion Molecule-1