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.

PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors / S. Minucci, S. Monestiroli, S. Giavara, S. Ronzoni, F. Marchesi, A. Insinga, D. Diverio, P. Gasparini, M. Capillo, E. Colombo, C. Matteucci, F. Contegno, F. Lo-Coco, E. Scanziani, A. Gobbi, P. Pelicci. - In: BLOOD. - ISSN 0006-4971. - 100:8(2002 Oct 15), pp. 2989-2995.

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

S. Minucci;E. Colombo;E. Scanziani;P. Pelicci
2002

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.
retinoic acid; transgenic mice; alpha; expression; cells; differentiation; morphology; sequences; diagnosis; product
Settore BIO/11 - Biologia Molecolare
15-ott-2002
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/207599
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