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| Status |
Public on Jul 29, 2010 |
| Title |
RARA haploinsufficiency modestly influences the phenotype of APL. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
RARA haploinsufficiency is an invariable consequence of t(15;17) reciprocal translocations in acute promyelocytic leukemia (APL). Furthermore, retinoids and RARA activity have been implicated in hematopoietic self-renewal, lineage commitment and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis we crossed RARA+/- mice with mice expressing PML-RARA from the Cathepsin G locus (mCG-PR). We found that RARA haploinsufficiency cooperated with PML-RARA, only modestly influencing the pre-leukemic and leukemic phenotype. Bone marrow from mCG-PR+/- x RARA+/- mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation and an increased competitive advantage following transplantation. RARA haploinsufficiency did not alter mCG-PR dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; mCG-PR+/- x RARA+/- mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL arising in these mice was responsive to ATRA, and had virtually no differences in expression profiling compared to tumors arising in mCG-PR+/- x RARA+/+ mice. These phenotypes were dependent on PML-RARA activity, since they were not detected in RARA+/- mice in the absence of the mCG-PR transgene. These data show that RARA haploinsufficiency (like PML haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis and phenotype of APL in mice, but that PML-RARA is the driver of t(15;17) APL.
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| Overall design |
RARA+/- mice were crossed with mice expressing PML-RARA from Cathepsin G locus (mCG-PR). Five leukemic mice were chosen from each of the mCG-PR+/-RARA+/- and mCG-PR+/-RARA+/+ strains and total RNA extracted from the spleen samples were analyzed using Affymetrics Mouse Exon 1.0 platform
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| Contributor(s) |
Welch JS, Klco JM, Chambon P, Varghese N, Nagarajan R, Ley TJ |
| Citation(s) |
21190992 |
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| Submission date |
Jul 28, 2010 |
| Last update date |
Mar 03, 2017 |
| Contact name |
Nobish Varghese |
| E-mail(s) |
[email protected]
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| Organization name |
Washington University in St.Louis
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| Street address |
4444 Forest Park Ave.
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| City |
StLouis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL6193 |
[MoEx-1_0-st] Affymetrix Mouse Exon 1.0 ST Array [probe set (exon) version] |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA131353 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE23291_RAW.tar |
228.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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