Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF–RAR α and NPM–RAR α

Abstract

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RAR␣ and one of four fusion partners: PML, PLZF, NPM, and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo, we generated transgenic mice with PLZF-RAR␣ and NPM-RAR␣. PLZF-RAR␣ transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM-RAR␣ transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RAR␣ transgenic mice, those from NPM-RAR␣ transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0.01 M, 0.1 M, and 1.0 M for RAR␣-RXR␣, NPM-RAR␣, and PML-RAR␣, respectively, but not observed for PLZF-RAR␣ even in the presence of 10 M ATRA. We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expressing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RAR␣ and NPM-RAR␣ and the importance of fusion receptor͞corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.Acute promyelocytic leukemia (APL) is characterized in most patients by accumulation of promyelocytes containing a specific chromosomal translocation t(15;17) and a unique sensitivity to all-trans-retinoic acid (ATRA) treatment (1, 2). There have been three variant translocations reported, including t(11;17)(q23;q21), t(5;17)(q32;q21), and t(11;17)(q13;q21). These chromosomal translocations invariably involve the RAR␣ (retinoic acid receptor ␣) gene on chromosome 17, and the PML

Review: genetic models of acute myeloid leukaemia

“…In particular, the human cathepsin-G (hCG) (Grisolano et al, 1994), MRP8 (Brown et al, 1997) and CD11b (Early et al, 1996) promoters were employed resulting in explicit expression of cDNA in a number of myeloid compartments, and varying disease phenotypes. Transgenic mice with NPM/RARa (Cheng et al, 1999), PML/RARa, PLZF/RARa and NuMa/RARa targeted to the promyelocytic compartment by the hCG vector exhibited diverse inter-and intra-specific phenotypes. The hCG-PML/RARa model mimicked the human APL phenotype as distinguished by promyelocytic accumulation in the bone marrow, extensive infiltration of leukaemic blasts preceded by protracted myeloproliferative disorders and exhibited complete, although transient, remission upon retinoic acid administration (Brown et al, 1997;Grisolano et al, 1997;He et al, 1997).…”

“…The APL variant of human AML is characterized by a differentiation block leading to an accumulation of promyelocytes, coagulation abnormalities, chromosomal translocations (Grisolano et al, 1997), PLZF/RARa t(11;17) (He et al, 1998;Cheng et al, 1999), nucleolar phosphoprotein NPM/RARa t(5;17) (Cheng et al, 1999), nuclear mitotic apparatus protein NuMA/RARa t(11;17)(q13;q21) (Sukhai et al, 2004) and Cyclin A1 (Liao et al, 2001) were generated with expression of exogenous cDNA directed exclusively to the myeloid compartment under regulation of human-specific promoter sequences. In particular, the human cathepsin-G (hCG) (Grisolano et al, 1994), MRP8 (Brown et al, 1997) and CD11b (Early et al, 1996) promoters were employed resulting in explicit expression of cDNA in a number of myeloid compartments, and varying disease phenotypes.…”

Transcriptional regulation in acute promyelocytic leukemia

“…It should be noted, however, that the network of protein ± protein interactions between the corepressors and both moieties of the fusion protein appears to be very complex and further validation of this model requires detailed analysis of these interactions both in vitro and in APL cells. Finally, this paradigm may be applied to other variant X-RARa fusion proteins such as NPM-RARa, whose biochemical and functional properties closely resemble those of PML-RARa (Cheng et al, 1999;Redner et al, 2000).…”

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

“…RARα, i.e., chronic myeloid leukemia (CML) (11), into APL (12). Moreover, the presence of RARα-PLZF increases the proliferation and resistance to RA treatment in double transgenic mice (12).…”