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RNAseq of human B-ALL cell lines following RUNX1 or CBFb knock-down

ABSTRACT: Five B-ALL cell lines representing major genetic subtypes were transfected with shRNAs targeting components of the core binding factor (CBF) complex. Five days after transfection, viable, shRNA-expressing cells were sorted and RNA was harvested. RNAseq was performed and knock-down samples compared to non-targeting controls.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Jason Wray

PROVIDER: E-MTAB-10329 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability.

Wray Jason P JP Deltcheva Elitza M EM Boiers Charlotta C Richardson Simon Е SЕ Chhetri Jyoti Bikram JB Brown John J Gagrica Sladjana S Guo Yanping Y Illendula Anuradha A Martens Joost H A JHA Stunnenberg Hendrik G HG Bushweller John H JH Nimmo Rachael R Enver Tariq T

Nature communications 20221121 1

The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as ...[more]

PMID: 36411286

Similar Datasets

RNA-seq following shRNA-mediated knock-down of ETV6-RUNX1 in the B-ALL cell line Reh

Project description:Stable derivatives of the Reh cell line carrying inducible shRNAs were generated by transducing with lentivirus harbouring the pTRIPZ vector and enabling doxycycline-inducible expression of shRNAs together with an RFP reporter. Two independent lines carrying different shRNAs targeting ETV6 or a vector control were generated. Cells were treated for 0 or 7 days with doxycycline, and harvested for bulk RNA-seq.

2022-04-10 | E-MTAB-10308 | biostudies-arrayexpress

Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [microarray]

Project description:Neurofibromatosis type 1 (NF1) patients are predisposed to develop neurofibromas but the underlying molecular mechanism(s) of neurofibromagenesis are not fully understood. We showed that dual genetic deletion of Runx1 (Rx1) and Runx3 (Rx3) in Schwann cells (SCs) and Schwann cell precursors (SCPs) significantly delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to tumor initiation. Knockdown of Pmp22 with shRNAs increased Rx1fl/fl;Rx3fl/fl;Nf1fl/fl;DhhCre sphere numbers and enabled significantly more neurofibroma like micro-lesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased proliferation. Mechanistically, Rx1/3 regulated alterative Pmp22 promoter usage and reduced post transcriptional expression of Pmp22. Finally, pharmacological inhibition of Runx/core binding factor beta (Cbf-β) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a novel signaling pathway involving Rx1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of Runx/Cbf-β interaction might provide a novel therapy for neurofibroma patients.

2019-05-01 | GSE122773 | GEO

Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [ATAC-seq]

2019-05-01 | GSE122776 | GEO

Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [ChIP-seq]

2019-05-01 | GSE122775 | GEO

Runx1 and Runx3 cooperatively repress Pmp22 to drive neurofibromagenesis [RNA-seq]

2019-05-01 | GSE122774 | GEO

Accelerated leukemogenesis by truncated CBFb-SMMHC defective in high-affinity binding with RUNX1

Project description:Dominant RUNX1 inhibition has been proposed as a common pathway for CBF-leukemia. CBFb-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). We generated knock-in mice expressing CBFb-SMMHC with a HABD deletion, CBFb-SMMHCd179-221. These mice developed leukemia highly efficiently, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. To identify changes in gene expression with the deletion of the HABD, we compared the gene expression profile in leukemia samples from mice expressing CBFb-SMMHCd179-221 with those from mice expressing full length CBFb-SMMHC.

2011-03-29 | GSE21155 | GEO

Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11.

Project description:It is known that CBFB-MYH11, the fusion gene generated by inversion of chromosome 16 in human acute myeloid leukemia, is causative for oncogenic transformation. However, the mechanism by which CBFB-MYH11 initiates leukemogenesis is not clear. Previously published reports showed that CBFB-MYH11 dominantly inhibits RUNX1 and CBFB, and such inhibition has been suggested as the mechanism for leukemogenesis. Here we show that Cbfb-MYH11 caused Cbfb/Runx1 repression-independent defects in both primitive and definitive hematopoiesis. During primitive hematopoiesis, Cbfb-MYH11 delayed differentiation characterized by sustained expression of Gata2, Il1rl1, and Csf2rb, a phenotype not found in Cbfb and Runx1 knockout mice. Expression of Cbfb-MYH11 in the bone marrow induced the accumulation of abnormal progenitor-like cells expressing Csf2rb in preleukemic mice. The expression of all 3 genes was detected in most human and murine CBFB-MYH11(+) leukemia samples. Interestingly, Cbfb-MYH11(+) preleukemic progenitors and leukemia-initiating cells did not express Csf2rb, although the majority of leukemia cells in our Cbfb-MYH11 knockin mice were Csf2rb(+). Therefore Csf2rb can be used as a negative selection marker to enrich preleukemic progenitor cells and leukemia-initiating cells from Cbfb-MYH11 mice. These results suggest that Cbfb/Runx1 repression-independent activities contribute to leukemogenesis by Cbfb-MYH11.

| S-EPMC2826765 | biostudies-literature

Accelerated leukemogenesis by truncated CBFb-SMMHC defective in high-affinity binding with RUNX1

2011-03-29 | E-GEOD-21155 | biostudies-arrayexpress

Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells.

Project description:Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-? (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.

| S-EPMC5709397 | biostudies-literature

Identification of Zdhhc20 knock-down cell palmitome

Project description:An shRNA screen to search for the mediators of pancreatic cancer metastasis identified palmitoyl transferase ZDHHC20 as a protein that mediates this process by promoting the outgrowth of metastatic cells in vivo. We sought to identify the changes in the palmitome of the cells expessing scrambled shRNA or shRNAs targeting Zdhhc20.

2023-02-09 | PXD038048 | Pride

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