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FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome

ABSTRACT: FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome

PROVIDER: PRJNA658804 | ENA |

REPOSITORIES: ENA

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FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome

Project description:This experiment is assocaited with a publication defining a tumor supressor role of FBXO11 in the transformation of MDS. We observe decreased expression of FBXO11 is associated with transformation to secondary AML.

2020-08-24 | GSE156708 | GEO

FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome.

Project description: Not available

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Pseudouridine-modified tRNA fragments repress malignant protein synthesis and predict leukemic progression in myelodysplastic syndrome

Project description:Transfer RNA (tRNA)-derived fragments (tRF) are emerging small noncoding (nc) RNAs that, while commonly altered in cancer, have poorly defined roles in tumorigenesis. Here we show that pseudouridylation (Ψ) of a stem-cell-enriched tRF subtype, mTOG, selectively inhibits malignant protein synthesis programs, thereby promoting engraftment and differentiation of myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC). Building on evidence that mTOG-Ψ target the polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed HDX-MS to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains in PABPC1. Mechanistically, this hinders the recruitment of the translational co-activator PABPC1-interacting protein 1 (PAIP1) and strongly represses translation of transcripts sharing 5’UTR pyrimidine-enriched sequences (PES), including 5’ terminal oligopyrimidine tracts (TOP) that encode protein machinery components, and are frequently altered in cancer. Significantly, mTOG dysregulation leads to aberrantly increased 5’PES mRNA translation in malignant MDS-HSPC and is clinically associated with leukemic transformation and reduced patient survival. Taken together, these results define a critical role for tRF and Ψ in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukemia.

2021-12-20 | PXD023122 | Pride

The signaling axis atypical protein kinase C l/i-Satb2 mediates leukemic transformation of B-cell progenitors

Project description:Oncogene driven transformation of leukemic progenitors results in B-acute lymphoblastic leukemia. Genetic deletions at specific hotspots are driven by recombination of epigenetically repressed loci and cause B cell transformation, and epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. The upstream signals driving epigenetic silencing have not been elucidated. BCR-ABL leukemias are initiated by leukemic stem cells/progenitors, and their modeling in vivo represents an opportunity for the identification of the epigenetic progress contributing to lineage leukemogenesis. We have found that primary human and murine BCR-ABL+ leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCz behaves as a leukemic suppressor, aPKCl/i is critically required for oncogenic progenitor proliferation, survival, and B cell differentiation arrest, but not for normal B cell lineage differentiation. We found that in vitro and in vivo B cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKCl/i-dependent Etv5/Satb2 chromatin repressive signaling complex. Thus genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias in vitro and in vivo. Therefore, the aPKCl/i-SATB2 signaling cascade is required for leukemic BCR-ABL+ B-cell progenitor transformation and is amenable to non-BCR-ABL kinase inhibition.

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HOXA9 Reprograms the Enhancer Landscape During Leukemic Transformation

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Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

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Genetic changes during leukemic transformation to secondary acute myeloid leukemia from myeloproliferative neoplasms

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PML-RARa induces dynamic changes in genome architecture during leukemic transformation

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Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

Project description:Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

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