title: PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors.
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.
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation; D002470:Cell Survival; D006410:Hematopoiesis / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000502:physiology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012190:Retroviridae; D015996:Survival Rate; D013997:Time Factors; D014162:Transfection
chemical_list: D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011994:Recombinant Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein