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
BACKGROUND
Acute graft-versus-host disease (aGvHD) remains a major complication after allogeneic hematopoietic cell transplantation (alloHCT). Adoptive regulatory T-cell (Treg) therapy may suppress alloreactive T-cell responses, but clinical implementation has been limited by donor-specific manufacturing, prolonged ex vivo expansion, and logistical complexity.
OBJECTIVE
We developed ATreg, a cell therapy product consisting of gp120-activated, polyclonal Tregs derived from HLA-unmatched third-party donors. The primary objective was to assess the safety, tolerability and toxicity of ATreg, hypothesizing that this would be feasable and safe for aGvHD prevention early after alloHCT in patients with hematologic malignancies.
STUDY DESIGN
ATreg-001 is a first-in-human, prospective, open-label, single-arm, multi-center phase 1/2 trial (EU CT number 2024-516599-14-00) conducted at four German centers (Mainz, Dresden, Münster, Dortmund). ATreg was generated from standard non-mobilized apheresis products by Treg isolation followed by 16 hours of gp120-mediated activation in the presence of IL-2, without ex vivo expansion, thereby enhancing suppressive function and (potentially) enabling a therapeutic effect at substantially lower Treg doses. Ten patients received ATreg at 0.1-1.0 × 10⁶ cells/kg body weight on day +10 ± 5 after alloHCT, in addition to standard GvHD prophylaxis, in a dose-escalation design across three cohorts. ATreg was administered within 24 hours after manufacturing. The primary endpoint was the type, incidence, and severity of ATreg-related serious adverse events within 14 days after administration. Secondary endpoints included manufacturing feasibility, aGvHD incidence/severity within 100 days, engraftment, and infections.
RESULTS
ATreg administration was well tolerated, with no infusion-related toxicities or other safety signals attributable to ATreg. All treated patients achieved hematopoietic engraftment and full donor chimerism. Within 100 days after alloHCT, no grade 3-4 aGvHD occurred, the cumulative incidence of grade 2-4 aGvHD was 10%, and no non-relapse mortality was observed.
CONCLUSION
These first clinical data support the feasibility and favorable safety profile of ATreg, a third-party, gp120-activated Treg product requiring no ex vivo expansion, and warrant further evaluation in larger prospective clinical trials.
MAIN POINTS
A. Tuettenberg, L. Ruhnke, J. Schlöder et al.· Transplantation and Cellular...· 0 citations
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