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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2001-11-0089.
Submitted November 28, 2001
Accepted June 6, 2002
PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors
Saverio Minucci, Silvia Monestiroli, Sabrina Giavara, Simona Ronzoni, Francesco Marchesi, Alessandra Insinga, Daniela Diverio, Patrizia Gasparini, Manuela Capillo, Emanuela Colombo, Cristian Matteucci, Francesco Contegno, Francesco Lo Coco, Eugenio Scanziani, Alberto Gobbi, and Pier G Pelicci*
Dept of Experimental Oncology, European Institute of Oncology, Milan, Italy; Dept of Physiology and General Biochemistry, University of Milan, Milan, Italy
Dept of Experimental Oncology, European Institute of Oncology, Milan, Italy
Department of Veterinary Pathology, School of Veterinary Medicine, University of Milan, Milan, Italy
Dept of Human Biotechnology and Hematology, University of Rome, Rome, Italy
IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
Dept of Experimental Oncology, European Institute of Oncology, Milan, Italy; IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
* Corresponding author; email: pgpelicci{at}ieo.it.
Acute Promyelocytic Leukemia (APL) is associated with chromosomal translocations resulting in fusion proteins of the retinoic acid receptor (RAR). Here, we report a novel murine model system for APL, based on the transduction of purified murine hematopoietic progenitors (lin-) using high-titer retroviral vectors encoding PML-RAR, and the green fluorescent protein (GFP) as a marker. PML-RAR-expressing lin- cells were impaired in their ability to undergo terminal myeloid differentiation, and showed increased proliferative potential in vitro. Inoculation of transduced lin- cells into syngeneic, irradiated mice resulted in the development of retinoic acid-sensitive promyelocytic leukemias at high frequency (more than 80%) and short latency (approximately 4 months). Morphological and immunophenotypic analysis revealed no gross abnormalities of the pre-leukemic bone marrows. However, hematopoietic progenitors from PML-RAR pre-leukemic mice showed a severe impairment in their ability to undergo myeloid differentiation in vitro. This result, together with the mono- or oligo-clonality of the leukemic blasts, supports a "multiple-hit" model, where the fusion protein causes a "pre-leukemic" phase, and leukemia occurs after additional genetic lesions. This model system faithfully reproduces the main characteristics of human APL, and represents a versatile tool for the in vitro and in vivo study of mechanisms of leukemogenesis, and the design of protocols for differentiation treatment.
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