High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARalpha expression.
Transgenic mice expressing PML-RARalpha in early myeloid cells under control of human cathepsin G regulatory sequences all develop a myeloproliferative syndrome, but only 15% to 20% develop acute promyelocytic leukemia (APL) after a latent period of 6 to 14 months. However, this transgene is expressed at very low levels in the bone marrow cells of transgenic mice. Because the transgene includes only 6 kb of regulatory sequences from the human cathepsin G locus, we hypothesized that sequences required for high-level expression of the transgene might be located elsewhere in the cathepsin G locus and that a knock-in model might yield much higher expression levels and higher penetrance of disease. We, therefore, targeted a human PML-RARalpha cDNA to the 5' untranslated region of the murine cathepsin G gene, using homologous recombination in embryonic stem cells. This model produced a high-penetrance APL phenotype, with more than 90% of knock-in mice developing APL between 6 and 16 months of age. The latent period and phenotype of APL (including a low frequency of an interstitial deletion of chromosome 2) was similar to that of the previous transgenic model. Remarkably, however, the expression level of PML-RARalpha in bone marrow cells or APL cells was less than 3% of that measured in the low-penetrance transgenic model. Although the explanation for this result is not yet clear, one hypothesis suggests that very low levels of PML-RARalpha expression in early myeloid cells may be optimal for the development of APL in mice.
Washington University, Division of Oncology, 660 S Euclid Ave, Campus Box 8007, St Louis, MO 63110-1093, USA.
Peter
P
Westervelt
Andrew A
AA
Lane
Jessica L
JL
Pollock
Kristie
K
Oldfather
Matthew S
MS
Holt
Drazen B
DB
Zimonjic
Nicholas C
NC
Popescu
John F
JF
DiPersio
Timothy J
TJ
Ley
D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D056649:Cathepsin G; D002403:Cathepsins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D019683:Penetrance; D012333:RNA, Messenger / Q000032:analysis; D011995:Recombination, Genetic; D012697:Serine Endopeptidases; D014212:Tretinoin / Q000494:pharmacology
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D015415:Biomarkers; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse