The DNA-helicase HELLS drives ALK ALCL proliferation by the transcriptional control of a cytokinesis-related program.

TitleThe DNA-helicase HELLS drives ALK ALCL proliferation by the transcriptional control of a cytokinesis-related program.
Publication TypeJournal Article
Year of Publication2021
AuthorsTameni A, Sauta E, Mularoni V, Torricelli F, Manzotti G, Inghirami G, Bellazzi R, Fragliasso V, Ciarrocchi A
JournalCell Death Dis
Volume12
Issue1
Pagination130
Date Published2021 01 27
ISSN2041-4889
KeywordsCell Line, Tumor, Cell Proliferation, Cytokinesis, DNA Helicases, Humans, Lymphoma, Large-Cell, Anaplastic, Transcriptional Activation, Transfection
Abstract

Deregulation of chromatin modifiers, including DNA helicases, is emerging as one of the mechanisms underlying the transformation of anaplastic lymphoma kinase negative (ALK) anaplastic large cell lymphoma (ALCL). We recently identified the DNA-helicase HELLS as central for proficient ALKALCL proliferation and progression. Here we assessed in detail its function by performing RNA-sequencing profiling coupled with bioinformatic prediction to identify HELLS targets and transcriptional cooperators. We demonstrated that HELLS, together with the transcription factor YY1, contributes to an appropriate cytokinesis via the transcriptional regulation of genes involved in cleavage furrow regulation. Binding target promoters, HELLS primes YY1 recruitment and transcriptional activation of cytoskeleton genes including the small GTPases RhoA and RhoU and their effector kinase Pak2. Single or multiple knockdowns of these genes reveal that RhoA and RhoU mediate HELLS effects on cell proliferation and cell division of ALKALCLs. Collectively, our work demonstrates the transcriptional role of HELLS in orchestrating a complex transcriptional program sustaining neoplastic features of ALKALCL.

DOI10.1038/s41419-021-03425-0
Alternate JournalCell Death Dis
PubMed ID33504766
PubMed Central IDPMC7840974
Grant ListP01 CA229100 / CA / NCI NIH HHS / United States
Related Faculty: 
Giorgio Inghirami, M.D.

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