ESTABLISHMENT OF A RETINOIC ACID-RESISTANT HUMAN ACUTE PROMYELOCYTIC LEUKEMIA (APL) MODEL IN HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (HGM CSF) TRANSGENIC SEVERE COMBINED IMMUNODEFICIENCY (SCID) MICE

To understand the mechanisms and identify novel approaches to overcomi ng retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL ), we established the first human RA-resistant APL model in severe com bined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL ce ll line established in our laboratory, were transplanted into human gr anulocyte-macrophage colony-stimulating factor (GM-CSF)-producing SCID (hGMTg SCID) mice and inoculated cells formed subcutaneous tumours in all hGMTg SCID mice, but not in the non-transgenic control SCID mice. Single-cell suspensions (UF-1/GMTg SCID cells) were similar in morpho logical, immunological, cytogenetic and molecular genetic features to parental UF-1 cells, All-trans RA did not change the morphological fea tures of cells or their expression of CD11b. RA did not alter the grow th curve of cells as determined by MIT assay, suggesting that UF-1/GMT g SCID cells are resistant to RA, These results demonstrate that this is the first RA-resistant APL animal model that may be useful for inve stigating the biology of this myeloid leukaemia in vivo, as well as fo r evaluating novel therapeutic approaches including patients with RA-r esistant APL.