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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2001-11-0089.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2989-2995
NEOPLASIA
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 Giuseppe Pelicci
From the European Institute of Oncology, Department of
Experimental Oncology, Milan, Italy; Department of Physiology and
General Biochemistry, and Department of Veterinary Pathology, Hygiene
and Public Health, School of Veterinary Medicine, University of Milan,
Italy; IFOM-FIRC Institute of Molecular Oncology, Milan, Italy; and
Department of Human Biotechnology and Hematology, University of Rome
"La Sapienza," Rome, Italy.
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
promyelocytic leukemia-RAR (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 (> 80%) and
short latency (approximately 4 months). Morphologic and
immunophenotypic analysis revealed no gross abnormalities of the
preleukemic bone marrows. However, hematopoietic progenitors from
PML-RAR preleukemic mice showed a severe impairment in their ability to
undergo myeloid differentiation in vitro. This result, together with
the monoclonality or oligoclonality of the leukemic blasts, supports a
"multiple-hit" model, where the fusion protein causes a
"preleukemic" 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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