Functional characterization of snoRNA-derived RNA (sdRNA) expression in healthy hematopoiesis and acute myeloid leukemia

SnoRNAs are highly expressed in AML and play a role in leukemogenesis and leukemic maintenance. SnoRNAs can be further processed into snoRNA-derived RNAs (sdRNAs). Expression and implications of sdRNAs in AML and healthy hematopoiesis, however, remain largely elusive. We characterized sdRNA and snoRNA levels in hematopoietic stem cells (HSCs), healthy peripheral blood cells, and 159 AML patient samples at initial diagnosis. HSCs, 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-hostgene ratios were associated with 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, and could therefore represent biomarkers to identify those at-risk patients. High sd3’-RNA ratios were associated with clear alterations in oncogenic, inflammatory and immune response signalling. Forced expression of single sdRNAs, such as sd3’-SNORD78 and sd5’-SNORD93, enhanced clonogenic potential in AML. Total proteome and transcriptome analyses suggested NUDT21, a reported tumor suppressor with implications in inflammatory and immune response signalling, as novel target of sd3’-SNORD78. Our data introduces sdRNAs as effector molecules in healthy hematopoiesis and AML with mechanistic, diagnostic, as well as potential prognostic and therapeutic implications.