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

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 3

mPML-fPR does not grossly alter bone marrow progenitor populations, CFUs, or ex vivo myeloid differentiation.

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mPML-fPR does not grossly alter bone marrow progenitor populations, CFUs...
(A) Schema showing that mice were treated with 10 doses of tamoxifen (4 mg i.p. twice weekly for 5 weeks) and analyzed 2 weeks later. (B) mPML-fPR modestly decreased the percentage of Lin–cKit+Sca+ (KLS) cells but not the percentage of Lin–cKit+Sca–CD16/32+CD34+ (GMP), Lin–cKit+Sca–CD16/32–CD34+ (CMP), or Lin–cKit+Sca–CD16/32–CD34– (MEP) cells. KLS is expressed as the percentage of Lin– cells; the others are expressed as the percentage of Lin–cKit+Sca– cells. Results are from 4 independent mice in each genotype. Horizontal bars are the median value. (C) mPML-fPR did not alter the number of CFUs in the bone marrow cells when grown for 7 days in methylcellulose containing IL-3, IL-6, and SCF (average ± SD). (D) mPML-fPR did not alter the immunophenotype of cells maturing during the methylcellulose culture in C. After 1 week in culture, cells were collected from methylcellulose, washed, and stained as indicated. Representative results are from 2 experiments (average ± SD). Horizontal bars are the median value. (E) Acute exposure of ERT2-Cre+/– × mPML-PRflox+/– bone marrow cells to 4-hydroxytamoxifen (4-OH tam) (0.1 M or 1 M) modestly decreased the number of CFU-Ms and total CFUs. Bone marrow cells from mice without prior tamoxifen exposure were harvested and plated in methylcellulose, as above, containing increasing doses of 4-hydroxytamoxifen (average ± SD).