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Loss of C/EBP cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage

¹ Laboratory of Gene Therapy Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark
² Granulocyte Laboratory, Copenhagen University Hospital, 2100 Copenhagen, Denmark
³ Department of Stem Cell Biology, Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, 22184 Lund, Sweden
⁴ EMBL Mouse Biology Unit, 00016 Monterotondo, Italy

CORRESPONDENCE Claus Nerlov: nerlov{at}embl-monterotondo.it

CCAAT/enhancer binding protein (C/EBP) is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBP to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations—all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count—normally associated with AML—were absent. These results show that disrupting the cell cycle regulatory function of C/EBP is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.

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