Abstract
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.
Highlights
The fusion gene PML-RARA is produced by t(15;17)(q22;q21), and is found only in the hematopoietic cells of patients with acute promyelocytic leukemia (APL)
In our mouse model of APL, PML-RARA is inserted into the 59 untranslated region of Ctsg, and the Ctsg locus regulates its expression [2]
To begin to define when PML-RARA expression is activated in this model during hematopoietic development, we first examined the expression of the Ctsg gene in all the compartments listed above, using young WT and Ctsg-PML-RARA
Summary
The fusion gene PML-RARA is produced by t(15;17)(q22;q21), and is found only in the hematopoietic cells of patients with acute promyelocytic leukemia (APL). When PML-RARA is expressed in mice using regulatory elements from the human or mouse cathepsin G gene (CTSG/Ctsg) or the human S100A8 (MRP8) promoter/enhancer, it can initiate APL; when RARA or PMLRARA are expressed in mouse bone marrow cells via retroviral transduction, both can decrease myeloid maturation and increase self-renewal [1,2,3,4]. Human APL is associated with differentiation arrest at the promyelocyte stage; in mouse models of the disease, this maturation arrest is less pronounced and varies between models, for reasons that are not yet clear. Because murine models of APL were designed to target PML-RARA expression to myeloidrestricted cells, we and others have suggested that myeloidrestricted disease might result from targeted expression of PML-. Human PML and murine Pml are expressed in early CD34+
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