Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.

The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility.

Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells.

Understanding clonal evolution and cancer development requires experimental approaches for characterizing the consequences of somatic mutations on gene regulation. However, no methods currently exist that efficiently link high-content chromatin accessibility with high-confidence genotyping in single cells. To address this, we developed Genotyping with the Assay for Transposase-Accessible Chromatin (GTAC), enabling accurate mutation detection at multiple amplified loci, coupled with robust chromatin accessibility readout. We applied GTAC to primary acute myeloid leukemia, obtaining high-quality chromatin accessibility profiles and clonal identities for multiple mutations in 88% of cells. We traced chromatin variation throughout clonal evolution, showing the restriction of different clones to distinct differentiation stages. Furthermore, we identified switches in transcription factor motif accessibility associated with a specific combination of driver mutations, which biased transformed progenitors toward a leukemia stem cell-like chromatin state. GTAC is a powerful tool to study clonal heterogeneity across a wide spectrum of pre-malignant and neoplastic conditions.

Factores de riesgo asociados a la conducta suicida en el adulto mayor / Risk factors associated with suicidal behavior in the elderly

RESUMEN Introducción: la conducta suicida es una de las cinco primeras causas de mortalidad en el mundo y se define como todo acto cometido en perjuicio propio de quien lo ejecuta, independientemente del grado de letalidad. Objetivo: describir algunos factores de riesgo asociados a la conducta suicida en el adulto mayor. Métodos: se realizó un estudio descriptivo, longitudinal y retrospectivo en el Policlínico «Octavio de la Concepción y la Pedraja¼, de Camajuaní. La población estuvo conformada por todos los pacientes adultos mayores, dispensarizados como riesgo de conducta suicida (140). Se realizó una revisión de las historias clínicas y se aplicaron: técnicas de observación, un cuestionario, una entrevista semiestructurada y una escala psicoafectiva. Resultados: la edad de los ancianos con conducta suicida es similar a los que no la tienen, U de Mann-Whitney Z = -1,008 y p = 0,313; el estado civil y la conducta suicida tienen una relación medianamente significativa con el sexo masculino p = 0,08, y muy significativa para el femenino p = 0,000. La relación es estadísticamente significativa para los factores depresión e intento previo, y altamente significativa para los problemas de pareja (55,2 %) y problemas familiares (51,7 %). Al relacionar gravedad de las circunstancias y seriedad de la intención, resultó nula para el ahorcamiento (55,6 %) y poca para la disección de vasos sanguíneos (50 %). Conclusiones: entre los factores de riesgo asociados se destacaron: depresión, intento previo, y drogo-dependencia; entre los métodos suaves o poco letales predominó la ingestión de fármacos en mujeres, y entre los métodos duros: el ahorcamiento y el envenenamiento en el sexo masculino.

ABSTRACT Introduction: suicidal behavior is one of the first five causes of mortality worldwide and is defined as any act committed to the detriment of the person who executes it, regardless of the degree of lethality. Objective: to describe some risk factors associated with suicidal behavior in the elderly. Methods: a descriptive, longitudinal and retrospective study was carried out at "Octavio de la Concepción y la Pedraja" Polyclinic from Camajuaní municipality. The population consisted of all elderly patients, classified as a risk of suicidal behavior (140). A review of the medical records was carried out; a questionnaire, a semi-structured interview, a psycho-affective scale and observation techniques were applied. Results: the age of the elderly with suicidal behavior is similar to those who do not, Mann-Whitney U Test Z = -1.008 and p = 0.313, m; marital status and suicidal behavior have a moderately significant relationship with male gender p = 0.08, and very significant for female gender p = 0.000. The relationship is statistically significant for depression and previous attempts, and highly significant for couple problems (55.2%) and family problems (51.7%). When relating the severity of the circumstances and the seriousness of the intention, it was null for hanging (55.6%) and few for dissection of blood vessels (50%). Conclusions: depression, previous attempts and drug dependence were among the associated risk factors; drug intake in women predominated between the mild or low-lethal methods, as well as, hanging and poisoning predominated in male gender among the hard methods.