[hCG-PLZF-RARalpha/hCG-RARalpha-PLZF transgenic mice developing into leukemia].
To investigate the potential role and the mechanism of PLZF-RARalpha/RARalpha-PLZF double fusion gene in the pathogenesis of acute promyelocytic leukemia (APL) in vivo at systematic biological level, PLZF-RARalpha/RARalpha-PLZF double transgenic mouse model was established by intercross; the integration and expression of fusion genes were analyzed by PCR and RT-PCR; the disease phenotype was detected by morphological and pathological examination of peripheral blood and bone marrow cells, as well as flow cytometry assays; the effects of ATRA with or without tricostatin A on bone marrow blast cells from PLZF-RARalpha/RARalpha-PLZF double TM were observed. The results showed that leukemia occurred in 5 PLZF-RARalpha/RARalpha-PLZF double TM 7, 7, 9, 11 and 11 months respectively, out of them two (40%) with classic APL features, the others (60%) with chronic myeloid leukemia through an observation period of 18 months. The leukemia occurrence of PLZF-RARalpha/RARalpha-PLZF TM was about 10%, which was similar to PLZF-RARalpha TM as that reported before. The latency was over 6 months, not earlier than PLZF-RARalpha TM only. No morphologic changes of PLZF-RARalpha/RARalpha-PLZF double TM blast cells to ATRA were observed, but increased cytoplasmic-nuclear ratio and nuclear condensation in bone marrow blast cells were found in combination of ATRA with tricostatin A. It is concluded that PLZF-RARalpha/RARalpha-PLZF double fusion gene transgenic mice have heterogeneity of pathogenesis. HDAC inhibitors such as trichostatin A, in combination with ATRA, induce differentiation of the blast/promyelocytic cells from PLZF-RARa/RARa-PLZF double TM, but not ATRA alone.
Chen
Li-Juan
LJ
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, The Shanghai Second Medical University, Shanghai 200025, China.
Dong
Ying
Y
Chen
Si-Yu
SY
Zhang
Long
L
Zhou
Guang-Biao
GB
Chen
Bing
B
Wang
Long
L
Chen
Zhu
Z
Chen
Sai-Juan
SJ
D000818:Animals; D018952:Antigens, CD34 / Q000097:blood; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010375:Pedigree; D019707:Receptors, Chemokine / Q000097:blood; D014212:Tretinoin / Q000494:pharmacology
D018952:Antigens, CD34; D006063:Chorionic Gonadotropin; C503133:Gr-1 protein, mouse; D006877:Hydroxamic Acids; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C492209:PLZF-RARalpha fusion protein, mouse; D019707:Receptors, Chemokine; C012589:trichostatin A; D014212:Tretinoin