Human stem cell model to study signal transduction and molecular regulation mechanisms in CML.
OBJECTIVE
To develop a primary human hematopoietic stem/progenitor cell model for chronic myeloid leukemia (CML) and study signal transduction and molecular regulation mechanisms in CML.


METHODS
We developed a human model of p210BCR/ABL positive CML by transducing normal human umbilical cord blood CD34+ cells with a retroviral vector containing the b3a2 bcr/abl cDNA. We also examined whether this model recreated the cellular phenotype of CML by assessing cell adhesion, cell migration, cell proliferation and cell survival.


RESULTS
We found that significantly more myeloid colony forming units grew from p210BCR/ABL expressing cells, adhesion of p210BCR/ABL expressing CD34+ cells to fibronectin was decreased but migration over fibronectin was enhanced compared with mock transduced CD34+ cells. In this model, we showed that the presence of p210BCR/ABL leads to elevated levels of p27kip in p210BCR/ABL expressing CD34+ cells. We also showed that multidrug resistance-1 (MDR-1) Pgp was upregulated in the p210BCR/ABL expressing cells which correlates with the expression of p210BCR/ABL.


CONCLUSIONS
This primary human CML model recreates most of the features of CML and provides a useful tool to study signal transduction and downstream molecular regulation drived by the p210BCR/ABL oncogene in normal CD34+ cells.
Fan
E
E
State Key Lab of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Science, Tianjin 300020, China.
Hu
Y
Y
Zhao
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D015973:Gene Expression Regulation, Leukemic; D016313:Genes, abl; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008840:Microfilament Proteins / Q000032:analysis; D009124:Muscle Proteins; D015398:Signal Transduction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018952:Antigens, CD34; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse