The role of fusion genes in acute myelogenous leukemia has been studied in leukemic cell lines and transgenic mice. These models bear intrinsic limitations due to the transformed nature of cell lines and the secondary genetic events that may occur in the animal We therefore directly studied the effects of acute promyelocytic leukemia (APL) PML/RARa fusion protein expression in human early hematopoietic progenitor cells (HPCs) purified from normal peripheral blood (PB) We took advantage of a novel gene transfer methodology, based on retroviral vector carrying a green 'fluorescent protein cDNA as a selectable marker: infected HPCs can be purified to homogeneity by cell sorting. HPCs expressing PML/RARa are rapidly induced îo differentiate to the promyelocytic stage and are largely blocked at this stage. These cells are markedly resistant to growth factor deprivation, and differentiate upon retinoic acid treatment Moreover unilineage or multilineage liquid suspension and clonogenic cultures demonstrated that PML/RARa expressing HPCs preferentially differentiate through the granulopoietic pathway ana are partially independent of growth factor stimulation. This has been formally demonstrated at single cell level by infecting two sibling HPCs with control or PML/RARa retroviruses. PML/RARa cells developed along the granulocytic pathway in the presence of saturating erythropoietin concentrations, that consistently channel control cells into erythroid differentiation. These findings indicate that the APL cell phentoype is determined by fusion gene expression: the leukemogenetic event may occur in eorly HPCs, whose development is determined by the oncogenic protein.
|Number of pages||1|
|Publication status||Published - 1998|
ASJC Scopus subject areas
- Cancer Research
- Cell Biology