Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation.

Bispecific antibodies targeting GPRC5D demonstrated promising efficacy in multiple myeloma, but acquired resistance usually occurs within a few months. Using a single-nucleus multi-omic strategy in three patients from the MYRACLE cohort (ClinicalTrials.gov registration: NCT03807128 ), we identified two resistance mechanisms, by bi-allelic genetic inactivation of GPRC5D or by long-range epigenetic silencing of its promoter and enhancer regions.

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability.

Background: Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective.

Methods: Here, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS).

In situ measurements of the physical characteristics of Titan's environment.

On the basis of previous ground-based and fly-by information, we knew that Titan's atmosphere was mainly nitrogen, with some methane, but its temperature and pressure profiles were poorly constrained because of uncertainties in the detailed composition. The extent of atmospheric electricity ('lightning') was also hitherto unknown. Here we report the temperature and density profiles, as determined by the Huygens Atmospheric Structure Instrument (HASI), from an altitude of 1,400 km down to the surface.