DNTT activation, TdT-aided gene length mutation, and better prognosis in ATG-based regimen allo-HSCT in AML.

This study aimed to investigate the relationship between anomalous DNA nucleotidylexotransferase (DNTT) activation and the mutagenesis of gene length mutations (LMs) in acute myeloid leukemia (AML), and the relevance of their prognosis in antithymocyte globulin (ATG)-based regimen allogeneic hematopoietic stem cell transplantation (allo-HSCT). A cohort of 578 AML cases was enrolled. Next-generation sequencing was performed to screen mutations of 86 leukemia driver genes. RNA-seq was used to analyze gene expression. Prognostic analysis was investigated in 239 AML cases who underwent ATG-based regimen allo-HSCT. We report a refined subtyping algorithm of LMs (type I-IV) based on sequence anatomy considering the TdT-aided mutagenesis mechanism. GC content adjacent to LM junctions, inserted nontemplate nucleotide bases, and DNTT expression analysis supported the DNTT activation and TdT-aided mutagenesis in type II/III LMs in the total AML cohort. Both single-variate and multivariate analyses showed a better overall survival of FLT3 type III compared to type I in a subset of ATG-based regimen allo-HSCT cases. The novel LM subtyping algorithm not only deciphers the etiology of the mutagenesis of LMs but also helps to fine-tune prognosis differentiation in AML. The possible prognostic versatility of this novel LM subtyping algorithm in terms of chemotherapy, targeted therapy, and allo-HSCT merits further investigation.

Enriched clonal hematopoiesis in seniors with dietary vitamin C inadequacy.

BACKGROUND: The anti-cancer effect of vitamin C (VC) has long been speculated, but studies yielded inconsistency. Recent studies reported that supraphysiological concentration of VC have therapeutic or prevention effects for myeloid malignancies with certain mutation signatures. There was a notable proportion of DAT (i.e., DNMT3A, ASXL1, and TET2) and dozens of other genes that mutate in age-related clonal hematopoiesis (ARCH). METHODS AND RESULTS: Through analyzing the plasma VC concentration and mutations of 21 genes in 215 senior volunteers, we revealed that ARCH is significantly associated with dietary plasma VC concentrations, especially TET2 mutations and non-DAT mutations. CONCLUSION: This study firstly disclosed the significant association between VC inadequacy and ARCH in the senior population. It provides evidence that physiological VC concentration has ARCH prevention effect. It will illuminate future explorations on the oral VC supplement in maintaining sound hematopoiesis, reversal ARCH, adjuvant therapy for myeloid malignancies, and prevention of other ARCH related comorbidities.

Targeted minor histocompatibility antigen typing to estimate graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is a critical complication after allogeneic haematopoietic stem cell transplantation induced by genetic differences in donor-recipient pairs. Rigorous HLA matching has reduced GVHD, but severe GVHD still occurs. Minor histocompatibility antigens (mHAs) are another source of GVHD inducers. We designed a multi-mHA panel with 35 valid mHA loci and retrospectively analyzed 391 donor-recipient pairs with the anticipation of implementing mHA typing into clinical practice to optimize donor selection. Results showed the total mismatching in mHA loci in this panel, as well as mismatching in the GVH direction in unmatched-related recipients (UMRs) were 1.8 times and 1.3 times as those in matched-sibling recipients (MSRs) (p = 4.1e-4, p = 0.012, respectively). There was no significant association between mHA loci mismatching and grades II-IV acute GVHD (aGVHD), III-IV aGVHD, extensive chronic GVHD (cGVHD), or relapse in neither group. UMRs had an increased cumulative incidence of II-IV aGVHD (p = 0.002), but there was no statistical difference of the incidences in severe aGVHD or cGVHD (p = 0.093; p = 0.930). This is a preliminary study to explore GVHD risks brought by mHA loci mismatching in both unmatched-related recipients and matched-full-sibling recipients. Our results confirmed that stringent HLA matching is the key to reduce the risks for GVHD.