The HELLS-MCM5 axis coordinates transcription-replication dynamics to preserve genomic integrity in ALK-negative anaplastic large cell lymphoma

The chromatin remodeler HELLS acts as a pleiotropic guardian of genomic integrity, orchestrating critical processes from DNA replication to DNA damage repair. In anaplastic large cell lymphoma (ALCL), HELLS functions as a transcriptional sentinel, fine-tuning chromatin accessibility and RNA polymerase II kinetics to sustain the oncogenic transcriptional landscape essential for lymphomagenesis. Here we show that HELLS preserves genomic stability and sustains ALK-negative ALCL proliferation by preventing transcription-replication conflicts. HELLS acts as a global regulator of R-loop homeostasis while transcriptionally sustaining MCM5, a core subunit of the replicative MCM2-7 complex, which locally restrains replication-transcription collisions at actively transcribed loci. Mechanistically, HELLS loss reduces MCM5 levels, triggering aberrant firing of origins within transcriptionally active regions and consequent collisions between replication forks and the transcription machinery. Being positioned distally from R-loop-enriched sites, HELLS and MCM5 cooperate to preserve genome integrity, with MCM5 acting as the effector that delivers locus-specific protection against replication-associated genomic instability. Pharmacological or genetic disruption of this axis increases R-loop burden and drastically reduces the survival of ALK-negative ALCL cells, providing a rationale for combination therapy. Collectively, the HELLS-MCM5 module emerges as a master coordinator of transcription-replication dynamics and a novel therapeutic vulnerability in aggressive lymphomas.