Project description:The transcriptional activating and repressive functions performed by Trithorax and Polycomb group complexes, respectively, are critical for to maintain cellular fates in ontogeny and in cancer. Here we report that leukemias initiated by a Trithorax-related oncogene, MLL-AF9, depend upon the Polycomb Repressive Complex 2 (PRC2) to sustain a transformed cellular state. RNAi mediated suppression of PRC2 subunits is sufficient to inhibit proliferation of MLL-AF9 leukemias, with little impact on growth of non-transformed cells. This requirement is partly due to PRC2-mediated transcriptional repression of several anti-self-renewal regulators, including Cdkn2a. These results suggest that, unlike the classical antagonism generally observed between Polycomb and Trithorax group proteins during development, the activities of these two pathways can cooperate to promote myeloid neoplasia. In order to understand downstream targets of PRC2 complex in MLL-AF9 leukemia, we performed array in murine MLL-AF9/NrasG12D cell line under the condition that two subunits of PRC2(Eed and Suz12) were suppressed by using shRNAs.
Project description:Remodeling of deregulated polycomb histone modifications promotes development of Down syndrome-related acute megakaryoblastic leukemia
| PRJDB17670 | ENA
Project description:The Polycomb Repressive Complex 2 Is Required For MLL-AF9 Leukemia
Project description:co-IP assays demonstrate that KDM6A is bound to WDR5, facilitating its association with the COMPASS complex and the polycomb repressive complex at the expected target loci.
Project description:Despite the impact of DNMT3A mutation in acute myeloid leukemia has been emphasized, the precise molecular mechanisms in leukemogenesis are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant hematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are down-regulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells. DNMT3A mutant also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), leading to transcriptional silencing of PU.1. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. Taken together, our results highlight the functional role of DNMT3A mutation, forming the basis for leukemia development.
Project description:Loss-of-function mutations in BCOR, subunit of the non-canonical Polycomb Repressive Complex 1.1 (PRC1.1), are frequently observed in acute myeloid leukemia (AML) and associate with adverse risk, but underlying mechanisms driving leukemogenesis remain elusive. Here, we find that BCOR is a bridging factor tethering the catalytic and chromatin-binding moieties of the PRC1.1 complex. Degron-mediated depletion of BCOR or KDM2B induces a rapid but time-dependent transcriptional induction, whereby early-upregulated genes have a distinct epigenetic profile compared to late-upregulated genes that are more heavily decorated with H3K27me3. Combined KDM2B degradation and PRC2 inhibition further amplifies gene induction suggesting distinct yet collaborative control over target genes. Strikingly, both JARID2/AEBP2 and SUZ12 knockout cells, completely devoid of PRC2 functionality, retain PRC1.1-loss induced transcriptional activation, underscoring that PRC1.1 can repress target genes independent of a downstream PRC2.2-canonical PRC1 repressive axis. Finally, combined targeting of PRC1.1 and PRC2 induces differentiation of leukemic cells emphasizing that co-targeting PRC1.1 and PRC2 represents a promising strategy to improve treatment of AML patients
Project description:The Bmi1 Polycomb protein is involved in the epigenetic repressive control of self renewal and survival of cancer initiating cells. In Chronic Myeloid Leukemia (CML), bmi1 expression increases gradually as the disease progresses from a chronic latent phase to a deadly blast crisis. We developped an inducible shRNA system to silence Bmi1 in the human K562 chronic myeloid leukemia (CML) cell line in order to identify new Bmi1-target genes. Gene profiling was performed on inducible shBmi1-K562 cells incubated without (P3-K562+shBMI1) or with doxycycline for 96h (P4-K562+shBMI1+doxycycline) using HG-U133 Plus2 Affymetrix Arrays.