Expression and Function of PML-RARA in the Hematopoietic Progenitor Cells of Ctsg-PML-RARA MiceReport as inadecuate

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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.

Author: Lukas D. Wartman , John S. Welch , Geoffrey L. Uy, Jeffery M. Klco, Tamara Lamprecht, Nobish Varghese, Rakesh Nagarajan, Timothy



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