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PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice
John S. Welch, … , Wenlin Yuan, Timothy J. Ley
John S. Welch, … , Wenlin Yuan, Timothy J. Ley
Published March 1, 2011
Citation Information: J Clin Invest. 2011;121(4):1636-1645. https://doi.org/10.1172/JCI42953.
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Research Article Oncology

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

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Abstract

Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that generates the fusion protein promyelocytic leukemia–retinoic acid receptor α (PML-RARA) in nearly all cases. Multiple prior mouse models of APL constitutively express PML-RARA from a variety of non-Pml loci. Typically, all animals develop a myeloproliferative disease, followed by leukemia in a subset of animals after a long latent period. In contrast, human APL is not associated with an antecedent stage of myeloproliferation. To address this discrepancy, we have generated a system whereby PML-RARA expression is somatically acquired from the mouse Pml locus in the context of Pml haploinsufficiency. We found that physiologic PML-RARA expression was sufficient to direct a hematopoietic progenitor self-renewal program in vitro and in vivo. However, this expansion was not associated with evidence of myeloproliferation, more accurately reflecting the clinical presentation of human APL. Thus, at physiologic doses, PML-RARA primarily acts to increase hematopoietic progenitor self-renewal, expanding a population of cells that are susceptible to acquiring secondary mutations that cause progression to leukemia. This mouse model provides a platform for more accurately dissecting the early events in APL pathogenesis.

Authors

John S. Welch, Wenlin Yuan, Timothy J. Ley

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Figure 4

mPML-fPR leads to inappropriate ex vivo self-renewal of bone marrow CFUs.

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mPML-fPR leads to inappropriate ex vivo self-renewal of bone marrow CFUs...
(A) Experiment schema showing that ERT2-Cre+/– × mPML-PRflox+/– mice and littermate controls were treated with tamoxifen (4 mg i.p. twice weekly for 10 doses). Bone marrow cells were plated in methylcellulose containing IL-3, IL-6, and SCF. At 7-day intervals, colony numbers were counted and cells were harvested and replated as indicated. (B) mPML-PRflox leads to inappropriate self-renewal when intercrossed with ERT2-Cre but not LysM-Cre. Representative results are from 2 experiments. Data points represent average and SD from 4 individual mice. (C) The mPML-fPR allele was associated with continued CFU activity in ERT2-Cre, but not LysM-Cre, bone marrow. The percentage of mPML-fPR alleles was assessed at each time point in B using qPCR. Data points represent results from individual mice. Horizontal bars are the median value.

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