Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.
We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBPalpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.
Bereshchenko
Oxana
O
EMBL Mouse Biology Unit, Via Ramarini 32, 00015 Monterotondo, Italy.
Mancini
Elena
E
Moore
Susan
S
Bilbao
Daniel
D
Månsson
Robert
R
Luc
Sidinh
S
Grover
Amit
A
Jacobsen
Sten Eirik W
SE
Bryder
David
D
Nerlov
Claus
C
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
D022763:CCAAT-Enhancer-Binding Protein-alpha