PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors
S Minucci, S Monestiroli, S Giavara… - Blood, The Journal …, 2002 - ashpublications.org
S Minucci, S Monestiroli, S Giavara, S Ronzoni, F Marchesi, A Insinga, D Diverio…
Blood, The Journal of the American Society of Hematology, 2002•ashpublications.orgAcute 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 …
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 …
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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