Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice.
Because PML-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many groups have speculated about whether its leukemic cell of origin is a committed myeloid precursor (e.g. a promyelocyte) versus an hematopoietic stem/progenitor cell (HSPC). We originally ta...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3466302?pdf=render |
| _version_ | 1818316893301243904 |
|---|---|
| author | Lukas D Wartman John S Welch Geoffrey L Uy Jeffery M Klco Tamara Lamprecht Nobish Varghese Rakesh Nagarajan Timothy J Ley |
| author_facet | Lukas D Wartman John S Welch Geoffrey L Uy Jeffery M Klco Tamara Lamprecht Nobish Varghese Rakesh Nagarajan Timothy J Ley |
| author_sort | Lukas D Wartman |
| collection | DOAJ |
| description | Because PML-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many groups have speculated about whether its leukemic cell of origin is a committed myeloid precursor (e.g. a promyelocyte) versus an hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg, and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice), are expressed in the purified KLS cells of these mice (KLS = Kit(+)Lin(-)Sca(+), which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Further, we demonstrate the transcriptional consequences of PML-RARA expression in Ctsg-PML-RARA mice in early myeloid development in other myeloid progenitor compartments [common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs)], which have a distinct gene expression signature compared to wild-type (WT) mice. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice and alters the transcriptional signature of these cells, it does not induce their self-renewal. In sum, these results demonstrate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function of multipotent progenitor cells. Finally, since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in this mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients. |
| first_indexed | 2024-12-13T09:28:40Z |
| format | Article |
| id | doaj.art-ecd7128d4bc543089c7d93944aa17360 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T09:28:40Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ecd7128d4bc543089c7d93944aa173602022-12-21T23:52:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4652910.1371/journal.pone.0046529Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice.Lukas D WartmanJohn S WelchGeoffrey L UyJeffery M KlcoTamara LamprechtNobish VargheseRakesh NagarajanTimothy J LeyBecause PML-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many groups have speculated about whether its leukemic cell of origin is a committed myeloid precursor (e.g. a promyelocyte) versus an hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg, and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice), are expressed in the purified KLS cells of these mice (KLS = Kit(+)Lin(-)Sca(+), which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Further, we demonstrate the transcriptional consequences of PML-RARA expression in Ctsg-PML-RARA mice in early myeloid development in other myeloid progenitor compartments [common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs)], which have a distinct gene expression signature compared to wild-type (WT) mice. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice and alters the transcriptional signature of these cells, it does not induce their self-renewal. In sum, these results demonstrate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function of multipotent progenitor cells. Finally, since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in this mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients.http://europepmc.org/articles/PMC3466302?pdf=render |
| spellingShingle | Lukas D Wartman John S Welch Geoffrey L Uy Jeffery M Klco Tamara Lamprecht Nobish Varghese Rakesh Nagarajan Timothy J Ley Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. PLoS ONE |
| title | Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. |
| title_full | Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. |
| title_fullStr | Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. |
| title_full_unstemmed | Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. |
| title_short | Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice. |
| title_sort | expression and function of pml rara in the hematopoietic progenitor cells of ctsg pml rara mice |
| url | http://europepmc.org/articles/PMC3466302?pdf=render |
| work_keys_str_mv | AT lukasdwartman expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT johnswelch expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT geoffreyluy expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT jefferymklco expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT tamaralamprecht expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT nobishvarghese expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT rakeshnagarajan expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice AT timothyjley expressionandfunctionofpmlrarainthehematopoieticprogenitorcellsofctsgpmlraramice |