PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors

Minucci, S. et al. (2002) PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors. Blood, 100(8), pp. 2989-2995. (doi: 10.1182/blood-2001-11-0089)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Marchesi, Dr Francesco
Authors: Minucci, S., Monestiroli, S., Giavara, S., Ronzoni, S., Marchesi, F., Insinga, A., Diverio, D., Gasparini, P., Capillo, M., Colombo, E., Matteucci, C., Contegno, F., Lo-Coco, F., Scanziani, E., Gobbi, A., and Pelicci, P.G.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Journal Name:Blood
ISSN:0006-4971
ISSN (Online):1528-0020

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