Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.

TY - JOUR

T1 - Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells.

AU - Kirstetter, Peggy

AU - Schuster, Mikkel B

AU - Bereshchenko, Oksana

AU - Moore, Susan

AU - Dvinge, Heidi

AU - Kurz, Elke

AU - Theilgaard-Mönch, Kim

AU - Månsson, Robert

AU - Pedersen, Thomas A

AU - Pabst, Thomas

AU - Schrock, Evelin

AU - Porse, Bo T

AU - Jacobsen, Sten Eirik W

AU - Bertone, Paul

AU - Tenen, Daniel G

AU - Nerlov, Claus

N1 - Keywords: Animals; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Granulocytes; Leukemia, Myelomonocytic, Acute; Macrophage-1 Antigen; Mice; Mice, Knockout; Models, Biological; Mutant Proteins; Myeloid Progenitor Cells; Neoplasm Transplantation; Neoplastic Stem Cells; Phenotype; Protein Isoforms; Proto-Oncogene Proteins c-kit

PY - 2008

Y1 - 2008

N2 - Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.

AB - Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.

U2 - 10.1016/j.ccr.2008.02.008

DO - 10.1016/j.ccr.2008.02.008

M3 - Journal article

C2 - 18394553

SN - 1535-6108

VL - 13

SP - 299

EP - 310

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -