SnoRNAs are highly expressed in AML and have implications in leukemogenesis and leukemic maintenance. SnoRNAs can be further processed into snoRNA-derived RNAs (sdRNAs). The role of sdRNAs in AML and healthy hematopoiesis remains largely elusive. We characterized sdRNA and snoRNA levels in hematopoietic stem and progenitor cells (HSPCs), healthy WBCs, and 159 intensively treated AML patient samples at initial diagnosis. HSPCs, healthy WBCs, and AML blasts could be differentiated by their sdRNA expression pattern in a cell-type-specific manner. In AML, high sd3'-RNA/snoRNA-host gene ratios were associated with an inverse patient outcome. Particularly, in NPM1-mutated patients with favorable risk stratification and good initial therapy response, high sd3'-RNA ratios identified a subgroup with inferior outcome. High sd3'-RNA ratios were associated with altered oncogenic, inflammatory, and immune response signaling. Forced expression of single sdRNAs, such as sd3'-SNORD78, sd3'-SNORD76, and sd5'-SNORD93, enhanced clonogenic potential in AML and drove sdRNA-specific gene expression signatures in both AML and healthy HSPCs. Exemplarily, we propose and characterize NUDT21, an important regulator of alternative polyadenylation and oncogenic gene expression, as a downstream target of sd3'-SNORD78 in AML. Our data introduce sdRNAs as standalone regulatory effector molecules in healthy hematopoiesis and AML.
R. Zinz, Christian Rohde, C. Pauli et al.· Leukemia· 0 citations
Patients with acute leukemias harboring translocations involving gene lysine methyltransferase 2A (KMT2A) have a poor prognosis due to chemotherapy resistance with rapid relapse following standard treatments. The resulting KMT2A fusion proteins dysregulate gene expression, leading to an upregulation of leukemogenic transcription factors such as HOXA9 and MEIS1, which drives leukemic transformation. Although Menin inhibitors are proving to be promising new therapeutics for patients with KMT2A-rearranged (KMT2Ar) acute leukemia, resistance mechanisms have already been described and new therapeutic approaches for this patient subgroup must be identified. Here, a genome-wide CRISPR/Cas9 screen in a KMT2Ar B-cell acute lymphoblastic leukemia (ALL) cell line identified the deubiquitinase USP22 as a novel regulator of MEIS1 protein stability. USP22 is a member of the Spt-Ada-Gcn5 acetyltransferase (SAGA) multiprotein complex, which has crucial functions in shaping the chromatin landscape and modulating transcription. Genetic depletion of USP22 impaired cellular growth and proliferation in KMT2Ar acute leukemia models. Chromatin immunoprecipitation revealed cooperative binding between USP22 and MEIS1 at critical oncogenic target genes suggesting that USP22 safeguards leukemogenic transcription by protecting MEIS1 from proteasomal degradation. Genetic or chemical inhibition of USP22 led to polyubiquitination of MEIS1 resulting in proteasomal degradation and downregulation of the expression of target genes. Our study identifies USP22 as a novel regulator of MEIS1 protein stability, that could potentially be exploited as a therapeutic target in the future in KMT2Ar leukemias.
Sarah Bröchtel, C. Schneider, Marius Müller et al.· Blood· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
