Michael Hallek | Search PubMed

PubMed2026

Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.

Caspase-3 (CASP3) and caspase-7 (CASP7) are the two major executioner caspases that are proteolytically activated by upstream initiator caspases. They possess almost indistinguishable activity, which has led to the overall view that these caspases have functionally redundant roles. Here, we generate knock-in mice expressing cleavage-resistant CASP3(D175A) or CASP7(D198A). Our results show that proteolytic activation of CASP3 and CASP7 is decisive for their activity in vivo and controls redundant processes during embryonic development as combined expression of both CASP3(D175A) and CASP7(D198A) causes embryonic lethality. In adult mice, however, activation of CASP3 and CASP7 controls different processes in different tissues, without the involvement of apoptosis. While CASP7 activation is required for male fertility by controlling spermatogenesis, CASP3 activation appears crucial for lymphoid tissue development by regulating interferon signalling. Our findings shed light on emerging roles of caspases in non-apoptotic processes and provide impetus for reconsidering their involvement in physiological and pathological conditions.

Animals↗

PubMed2026

MRD-2 in the GHSG HD21 trial assessed by a validated circulating tumor DNA sequencing assay.

Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor DNA (ctDNA) sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling time points, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista, a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma, to samples obtained from the German Hodgkin Study Group (GHSG) HD21 trial after 2 cycles of treatment (MRD-2) using a case-cohort design. Patients with positive MRD-2 result were at higher risk for relapse, progression, or death compared with MRD-2-negative patients (4-year progression-free survival [PFS], 36.7% vs 82.2%; hazard ratio, 5.3; 95% confidence interval, 2.0-13.8; P = .0008). After inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 results had 4-year PFS rates of 72.2% vs 95.3%. Combining MRD-2 with positron emission tomography after 2 cycles of BrECADD/eBEACOPP (PET-2) can identify patients at very low and patients at very high risk of relapse, progression, or death. In summary, these results suggest that MRD-2 assessment by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

Humans↗