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

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

Graphoepitaxial growth of CeO2 thin films on tilted-axes NdGaO3 substrates by pulsed laser deposition

CeO2 thin films were grown on NdGaO3 tilted-axes substrates by pulsed laser deposition (PLD) showing three-dimensional graphoepitaxial (3DGE) growth in the whole studied range of substrate tilt angles γ = 5-27º. Deviations from the tangent dependence can be divided into a systematic negative part and local deviations near certain film tilt angles. The systematic deviation may be explained as the effect of completely-strained coherent growth of the bottom layers of CeO2 film. Minimization of the surface energy near the small-index crystallographic planes (012) and (013) may account for the local deviations from the calculated dependence. The width of the rocking curve and the lattice constant variation for the 3DGE CeO2 films increase almost linearly with the substrate tilt angle until 19º and decrease for higher γ. At different deposition rates the 3DGE CeO2 film exhibits three possible structures: (i) relaxed completely oxygenated films at very low deposition rate, (ii) completely strained well-oxygenated films at moderate deposition rates, and (iii) oxygen-deficient films consisting of two layers at high deposition rates. The deviations of orientation of the film from the 3DGE formula are set by the lattice constant c in the direction normal to the (110) SICP of the substrate, which, in turn, depends on oxygen deficiency and the level of strain, introduced into the film by lattice mismatch with the substrate.publishe