Polycomb Repressive Complex 2 (PRC2) is a chromatin regulator with central roles in development and cancer. The canonical function of PRC2 is the tri-methylation of histone 3 on lysine residue 27. This epigenetic modification is associated with gene silencing. Both tumor suppressor and oncogenic functions have been reported for PRC2, depending on cellular context. In leukemia mediated by the leukemogenic fusion MLL-AF9, complete ablation of canonical PRC2 function by genetic inactivation of the core component Embryonic Ectoderm Development (Eed) or by combined pharmacological inhibition of the PRC2 methyltransferases EZH2 and EZH1 has a strong antileukemic effect, and this effect has been linked to derepression of the PRC2 target locus Cdkn2a. We asked whether inactivation of Cdkn2a is sufficient to restore leukemic activity of Eed-inactivated MLL-AF9 leukemia cells, using combined genetic inactivation of Cdkn2a and Eed. We found that Cdkn2a inactivation partially rescues in vitro and in vivo growth of Eed-inactivated MLL-AF9 cells. However, the growth of Eed-null Cdkn2a-null MLL-AF9 cells in the absence of Cdkn2a remained severely compromised in vitro and in vivo, compared to Eed-floxed Cdkn2a-null counterparts. RNAseq analysis revealed that several genes previously implicated in inefficient growth of MLL-AF9 transformed cells, including Gata2, Egr1 and Cdkn2b were derepressed as a consequence of Eed-inactivation. Furthermore, we found that direct binding targets of MLL-fusion proteins are negatively enriched in Eed-inactivated Cdkn2a-null MLL-AF9-transformed cells. Our data show that interference with PRC2 function affects MLL-AF9 mediated leukemogenesis by both Cdkn2a-dependent and Cdkn2a-independent mechanisms.
For the first time we show the effects of deuterium oxide on cell growth and vesicle transport in rat basophilic leukemia (RBL-2H3) cells. RBL-2H3 cells cultured with 15 moles/L deuterium showed decreased cell growth which was attributed to cells not doubling their DNA content. Experimental observations also showed an increase in vesicle speed for cells cultured in deuterium oxide. This increase in vesicle speed was not observed in deuterium oxide cultures treated with a microtubule-destabilizing drug, suggesting that deuterium oxide affects microtubule-dependent vesicle transport.
Rationale In virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We’ve previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells. Objective To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. Methods and results Brief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. Conclusions These data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.
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