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, Pier Giuseppe Pelicci

Research output: Contribution to journalArticle

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 pro liferative 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.

Original languageEnglish
Pages (from-to)2989-2995
Number of pages7
JournalBlood
Volume100
Issue number8
DOIs
Publication statusPublished - Oct 15 2002

ASJC Scopus subject areas

  • Hematology

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    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., & Pelicci, P. G. (2002). PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors. Blood, 100(8), 2989-2995. https://doi.org/10.1182/blood-2001-11-0089