Abstract
To understand the mechanisms and identify novel approaches to overcoming retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL), we established the first human RA-resistant APL model in severe combined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL cell line established in our laboratory, were transplanted into human granulocyte-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 morphological, immunological, cytogenetic and molecular genetic features to parental UF-1 cells. All-trans RA did not change the morphological features of cells or their expression of CD11b. RA did not alter the growth curve of cells as determined by MTT assay, suggesting that UF-1/GMTg SCID cells are resistant to RA. These results demonstrate that this is the first RA-resistant APL animal model that may be useful for investigating the biology of this myeloid leukaemia in vivo, as well as for evaluating novel therapeutic approaches including patients with RA-resistant APL.
Highlights
The retinoic acid (RA)-resistant acute promyelocytic leukaemia (APL) cell line (UF-1) wxas established in our laboratorx (Kizaki et al 1996a)
Endogenous serum human granulocyte-macrophage colony-stimulating factor (GM-CSF) lexels were detected in all hGMTg severe combined immunodeficiency (SCID) mice (6640-10 000 pg ml-') but not in any non-transgenic B-17-scid or C57B6/J (B6J) SCID mice (Table 1)
All of the tumours were composed of leukaemic cells: howexer. no obvious infiltration Axas obserxed in the major organs in both hGMNTg SCID and control B6J mice (Figure lA and B. and data not shown)
Summary
The RA-resistant APL cell line (UF-1) wxas established in our laboratorx (Kizaki et al 1996a). Human GMI-CSF transgenic )hGITg) SCID mice used in this study xxere newxly produced as described prexiously (Mixak-axa et al 1996). SCID mouse with diffuse infiltration of leukaemic cells. (C and D) Morphology of parental UF-1 (C) and UF-1/GMTg SCID cells (D). Single-cell suspensions (UF-1/GMTg SCID cells) were collected and cytospin slides were prepared and stained with Giemsa [original magnification x 1000 (C and D)]. A Tg mouse producing hGM-CSF in the sera born of two founder mice. Was crossed with B6J-scid to obtain hGM-CSF producing scidlscid offspring. The mice were maintained bv back-crossine with B6J-scid under specific pathogen-free conditions in our laboratory. Serum levels of human GM-CSF w-ere measured using an enzy-me-linked immunosorbent assay (ELISA) kit Leukaemic cell arowth Awas assessed by daily measurements of the dimension of subcutaneous nodules. Surviving mice were sacrificed at the end of the experiment and sectioned for microscopic examination of the tumour
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