TY - JOUR
T1 - A truncation mutant of Csf3r cooperates with PML-RARα to induce acute myeloid leukemia in mice
AU - Kunter, Ghada
AU - Woloszynek, Jill R.
AU - Link, Daniel C.
N1 - Funding Information:
We thank Timothy J. Ley (Washington University, St Louis, MO, USA) for generously providing the PML-RARα transgenic mice and Amgen (Thousand Oaks, CA, USA) for their generous gift of G-CSF and pegylated G-CSF. We thank the staff of the Siteman Cancer Center at Washington University’s Flow Cytometry core facility for their expert technical assistance. This work was supported by National Institutes of Health grants R01 CA136617 (D.C.L.) and K12 HL087107 (G.K.) .
PY - 2011/12
Y1 - 2011/12
N2 - Severe congenital neutropenia is associated with a marked propensity to develop myelodysplasia or acute myeloid leukemia (AML). Truncation mutations of CSF3R, encoding the granulocyte colony-stimulating factor receptor (G-CSFR), are associated with development of myelodysplasia/AML in severe congenital neutropenia. However, a causal relationship between CSF3R mutations and leukemic transformation has not been established. Herein, we show that truncated G-CSFR cooperates with the PML-RARα oncogene to induce AML in mice. Expression of truncated G-CSFR significantly shortens the latency of AML in a G-CSF-dependent fashion and it is associated with a distinct AML presentation characterized by higher blast counts and more severe myelosuppression. Basal and G-CSF-induced signal transducer and activator of transcription 3, signal transducer and activator of transcription 5, and extracellular signal-regulated kinase 1/2 phosphorylation were highly variable but similar in leukemic blasts expressing wild-type and truncated G-CSFR. These data provide new evidence suggesting a causative role for CSF3R mutations in human AML.
AB - Severe congenital neutropenia is associated with a marked propensity to develop myelodysplasia or acute myeloid leukemia (AML). Truncation mutations of CSF3R, encoding the granulocyte colony-stimulating factor receptor (G-CSFR), are associated with development of myelodysplasia/AML in severe congenital neutropenia. However, a causal relationship between CSF3R mutations and leukemic transformation has not been established. Herein, we show that truncated G-CSFR cooperates with the PML-RARα oncogene to induce AML in mice. Expression of truncated G-CSFR significantly shortens the latency of AML in a G-CSF-dependent fashion and it is associated with a distinct AML presentation characterized by higher blast counts and more severe myelosuppression. Basal and G-CSF-induced signal transducer and activator of transcription 3, signal transducer and activator of transcription 5, and extracellular signal-regulated kinase 1/2 phosphorylation were highly variable but similar in leukemic blasts expressing wild-type and truncated G-CSFR. These data provide new evidence suggesting a causative role for CSF3R mutations in human AML.
UR - http://www.scopus.com/inward/record.url?scp=81155135073&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2011.08.013
DO - 10.1016/j.exphem.2011.08.013
M3 - Article
C2 - 21911095
AN - SCOPUS:81155135073
VL - 39
SP - 1136
EP - 1143
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 12
ER -