PMID- 8755574
OWN - NLM
STAT- MEDLINE
DCOM- 19961029
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 93
IP  - 15
DP  - 1996 Jul 23
TI  - Transgenic expression of PML/RARalpha impairs myelopoiesis.
PG  - 7900-4
AB  - The translocation found in acute promyelocytic leukemia rearranges the 
      promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid 
      receptor alpha (RARalpha) on chromosome 17. This yields a fusion transcript, 
      PML/RARalpha, a transcription factor with reported dominant negative functions in 
      the absence of hormone. Clinical remissions induced with all-trans retinoic acid 
      (RA) treatment in acute promyelocytic leukemia are linked to PML/RARalpha 
      expression in leukemic cells. To evaluate the PML/RARalpha role in myelopoiesis, 
      transgenic mice expressing PML/RARalpha were engineered. A full-length 
      PML/RARalpha cDNA driven by the CD11b promoter was expressed in transgenic mice. 
      Expression was confirmed in the bone marrow with a reverse transcription PCR 
      assay. Basal total white blood cell and granulocyte counts did not appreciably 
      differ between PML/RARalpha transgenic and control mice. Cell sorter analysis of 
      CD11b+ bone marrow cells revealed similar CD11b+ populations in transgenic and 
      control mice. However, in vitro clonal growth assays performed on peripheral 
      blood from transgenic versus control mice revealed a marked reduction of myeloid 
      progenitors, especially in those responding to granulocyte/ macrophage 
      colony-stimulating factor. Granulocyte/macrophage colony-stimulating factor and 
      kit ligand cotreatment did not overcome this inhibition. Impaired myelopoiesis in 
      vivo was shown by stressing these mice with sublethal irradiation. Following 
      irradiation, PML/RARalpha transgenic mice, as compared with controls, more 
      rapidly depressed peripheral white blood cell and granulocyte counts. As 
      expected, nearly all control mice (94.4%) survived irradiation, yet this 
      irradiation was lethal to 45.8% of PML/RARalpha transgenic mice. Lethality was 
      associated with more severe leukopenia in transgenic versus control mice. 
      Retinoic acid treatment of irradiated PML/RARalpha mice enhanced granulocyte 
      recovery. These data suggest that abnormal myelopoiesis due to PML/RARalpha 
      expression is an early event in oncogenic transformation.
FAU - Early, E
AU  - Early E
AD  - Department of Medicine, Laboratory of Molecular Medicine, Sloan-Kettering 
      Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
FAU - Moore, M A
AU  - Moore MA
FAU - Kakizuka, A
AU  - Kakizuka A
FAU - Nason-Burchenal, K
AU  - Nason-Burchenal K
FAU - Martin, P
AU  - Martin P
FAU - Evans, R M
AU  - Evans RM
FAU - Dmitrovsky, E
AU  - Dmitrovsky E
LA  - eng
GR  - 1F32CA61646-01A1/CA/NCI NIH HHS/United States
GR  - CA55418/CA/NCI NIH HHS/United States
GR  - R01-62275-02/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cytokines)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Pml protein, mouse)
RN  - 0 (Promyelocytic Leukemia Protein)
RN  - 0 (RARA protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Rara protein, mouse)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Stem Cell Factor)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 143220-95-5 (PML protein, human)
RN  - 5688UTC01R (Tretinoin)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells
MH  - Cells, Cultured
MH  - Chromosomes, Human, Pair 15
MH  - Chromosomes, Human, Pair 17
MH  - Cytokines/pharmacology
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
MH  - Granulocytes/cytology/drug effects
MH  - Hematopoietic Stem Cells/cytology/drug effects/physiology
MH  - Humans
MH  - Leukemia, Promyelocytic, Acute/*genetics
MH  - Leukocyte Count/radiation effects
MH  - Mice
MH  - Mice, Transgenic
MH  - *Neoplasm Proteins
MH  - *Nuclear Proteins
MH  - Polymerase Chain Reaction
MH  - Promyelocytic Leukemia Protein
MH  - RNA, Messenger/biosynthesis
MH  - Receptors, Retinoic Acid/*biosynthesis/genetics
MH  - Retinoic Acid Receptor alpha
MH  - Stem Cell Factor/pharmacology
MH  - Transcription Factors/*biosynthesis/genetics
MH  - Transcription, Genetic
MH  - Translocation, Genetic
MH  - Tretinoin/pharmacology
MH  - Tumor Suppressor Proteins
PMC - PMC38846
EDAT- 1996/07/23 00:00
MHDA- 1996/07/23 00:01
PMCR- 1997/01/23
CRDT- 1996/07/23 00:00
PHST- 1996/07/23 00:00 [pubmed]
PHST- 1996/07/23 00:01 [medline]
PHST- 1996/07/23 00:00 [entrez]
PHST- 1997/01/23 00:00 [pmc-release]
AID - 10.1073/pnas.93.15.7900 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7900-4. doi: 
      10.1073/pnas.93.15.7900.