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

CCAAT/enhancer binding protein (C/EBP)alpha 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 alpha 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 alpha is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.

Bryder, DavidLund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups(Swepub:lu)med-dbr (författare)
Theilgaard-Monch, K (författare)
Hasemann, MS (författare)
Anderson, KristinaLund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)stem-kan (författare)
Damgaard, I (författare)
Jacobsen, Sten Eirik WLund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)stem-sja (författare)
Nerlov, C (författare)
ImmunologiForskargrupper vid Lunds universitet (creator_code:org_t)

Ingår i:Journal of Experimental Medicine: Rockefeller University Press202:1, s. 85-961540-95380022-1007

Av författaren/redakt...: Porse, BT; Bryder, David; Theilgaard-Monch ...; Hasemann, MS; Anderson, Kristi ...; Damgaard, I; visa fler...; Jacobsen, Sten E ...; Nerlov, C; visa färre...

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