Abstract
The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor α gene (RARα). To test the hypothesis that the chimera PMLRARα plays a role in leukemogenesis, we expressed a PMLRARα cDNA in myeloid cells of transgenic mice. PMLRARα transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRARα impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
| Original language | English |
|---|---|
| Pages (from-to) | 2551-2556 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 94 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 18 1997 |
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Keywords
- hematopoiesis
- retinoic acid
- t(15;17)
- transgenic mice
ASJC Scopus subject areas
- General
- Genetics
Cite this
A PMLRARα transgene initiates murine acute promyelocytic leukemia. / Brown, Diane; Kogan, Scott; Lagasse, Eric; Weissman, Irving; Alcalay, Myriam; Pelicci, Pier Giuseppe; Atwater, Susan; Bishop, J. Michael.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 6, 18.03.1997, p. 2551-2556.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A PMLRARα transgene initiates murine acute promyelocytic leukemia
AU - Brown, Diane
AU - Kogan, Scott
AU - Lagasse, Eric
AU - Weissman, Irving
AU - Alcalay, Myriam
AU - Pelicci, Pier Giuseppe
AU - Atwater, Susan
AU - Bishop, J. Michael
PY - 1997/3/18
Y1 - 1997/3/18
N2 - The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor α gene (RARα). To test the hypothesis that the chimera PMLRARα plays a role in leukemogenesis, we expressed a PMLRARα cDNA in myeloid cells of transgenic mice. PMLRARα transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRARα impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
AB - The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor α gene (RARα). To test the hypothesis that the chimera PMLRARα plays a role in leukemogenesis, we expressed a PMLRARα cDNA in myeloid cells of transgenic mice. PMLRARα transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRARα impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
KW - hematopoiesis
KW - retinoic acid
KW - t(15;17)
KW - transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=0030615230&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030615230&partnerID=8YFLogxK
U2 - 10.1073/pnas.94.6.2551
DO - 10.1073/pnas.94.6.2551
M3 - Article
C2 - 9122233
AN - SCOPUS:0030615230
VL - 94
SP - 2551
EP - 2556
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 6
ER -