First-line treatment of double-hit and triple-hit lymphomas: Survival and tolerance data from a retrospective multicenter French study.

Historically, double or triple hit lymphoma (DHL and THL) have poor outcomes with conventional chemotherapy, but there is currently no guideline. We report the French experience in managing DHL and THL in first line using collective data on both survival and tolerance. All consecutive patients with newly diagnosis of large B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements, as determined by FISH between January 2013 and April 2019 were included. Based on the eligibility criteria, 160 patients were selected among the 184 patients identified. With a median follow-up of 32 months, 2- and 4-year progression free survival (PFS) rates were 40% and 28% with R-CHOP compared with 57% and 52% with intensive chemotherapy (P = .063). There was no difference in overall survival (OS). For advanced stages, PFS was significantly longer with intensive chemotherapy than with R-CHOP (P = .029). There was no impact of autologous stem cell transplantation among patient in remission. For patients with central nervous system (CNS) involvement, the 2-year PFS and OS rate was 21% and 39%, vs 57% and 75% without CNS disease (P = .007 and P < .001). By multivariate analysis, elevated IPI score and CNS disease were strongly and independently associated with a poorer survival, whereas treatment was not significantly associated with OS. This is the largest series reporting the treatment of DHL and THL in Europe. The PFS was significantly longer with an intensive regimen for advanced stage, but no difference in OS, supporting the need for a prospective randomized trial.

Single-molecule nucleosome remodeling by INO80 and effects of histone tails.

Genome maintenance and integrity requires continuous alterations of the compaction state of the chromatin structure. Chromatin remodelers, among others the INO80 complex, help organize chromatin by repositioning, reshaping, or evicting nucleosomes. We report on INO80 nucleosome remodeling, assayed by single-molecule Foerster resonance energy transfer on canonical nucleosomes as well as nucleosomes assembled from tailless histones. Nucleosome repositioning by INO80 is a processively catalyzed reaction. During the initiation of remodeling, probed by the INO80 bound state, the nucleosome reveals structurally heterogeneous states for tailless nucleosomes (in contrast to wild-type nucleosomes). We, therefore, propose an altered energy landscape for the INO80-mediated nucleosome sliding reaction in the absence of histone tails.

The nuclear actin-containing Arp8 module is a linker DNA sensor driving INO80 chromatin remodeling.

Nuclear actin (N-actin) and actin-related proteins (Arps) are critical components of several chromatin modulating complexes, including the chromatin remodeler INO80, but their function is largely elusive. Here, we report the crystal structure of the 180-kDa Arp8 module of Saccharomyces cerevisiae INO80 and establish its role in recognition of extranucleosomal linker DNA. Arp8 engages N-actin in a manner distinct from that of other actin-fold proteins and thereby specifies recruitment of the Arp4-N-actin heterodimer to a segmented scaffold of the helicase-SANT-associated (HSA) domain of Ino80. The helical HSA domain spans over 120 Å and provides an extended binding platform for extranucleosomal entry DNA that is required for nucleosome sliding and genome-wide nucleosome positioning. Together with the recent cryo-electron microscopy structure of INO80Core-nucleosome complex, our findings suggest an allosteric mechanism by which INO80 senses 40-bp linker DNA to conduct highly processive chromatin remodeling.

The kinases LF4 and CNK2 control ciliary length by feedback regulation of assembly and disassembly rates.

BACKGROUND: Many of the diverse functions of cilia depend upon tight control of their length. Steady-state length reflects a balance between rates of ciliary assembly and disassembly, two parameters likely controlled by a length sensor of unknown identity or mechanism. RESULTS: A null mutation in Chlamydomonas CNK2, a member of the evolutionarily conserved family of NIMA-related kinases, reveals feedback regulation of assembly and disassembly rates. cnk2-1 mutant cells have a mild long-flagella (lf) phenotype as a consequence of reduced rates of flagellar disassembly. This is in contrast to the strong lf mutant lf4-7, which exhibits an aberrantly high rate of assembly. Cells carrying both mutations have even longer flagella than lf4-7 single mutants do. In addition to their high rate of assembly, lf4-7 mutants have a CNK2-dependent increase in disassembly rate. Finally, cnk2-1 cells have a decreased rate of turnover of flagellar subunits at the tip of the flagellum, demonstrating that the effects on disassembly are compensated by a reduced rate of assembly. CONCLUSIONS: We propose a model wherein CNK2 and LF4 modulate rates of disassembly and assembly respectively in a feedback loop that is activated when flagella exceed optimal length.