Journal Article

Expression and Function of PML-RARA in the Hematopoietic Progenitor Cells of Ctsg-PML-RARA Mice

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

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute promyeloid leukemia / Analysis / Animals / Base Sequence / Biological effects / Biology / Cancer / Cathepsin G - genetics / Cell Separation / Cells (biology) / Compartments / DNA Primers / Flow Cytometry / Gene expression / Gene Expression Profiling / Genes / Hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Immunology / Laboratories / Leukemia / Leukocytes (granulocytic) / Medicine / Mice / Monocytes / Neutrophils / Oncogene Proteins, Fusion - genetics / Oncology / Pathology / Polymerase Chain Reaction / Progenitor cells / Promyeloid leukemia / Regulatory sequences / Repopulation / Rodents / Stem cell transplantation / Stem cells / Transcription