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1.
Blood ; 141(10): 1105-1118, 2023 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-36493345

RESUMEN

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR-CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Síndrome de Down , Leucemia Mieloide , Animales , Niño , Humanos , Ratones , Aneuploidia , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Síndrome de Down/complicaciones , Síndrome de Down/genética , Leucemia Mieloide/genética , Isoformas de Proteínas/genética , Trisomía/genética
2.
Artículo en Alemán | MEDLINE | ID: mdl-37106056

RESUMEN

According to official statistics from the German long-term care insurance funds, around six out of every one hundred people with statutory health insurance are considered to be in need of long-term care. In this context, "need of long-term care" is defined according to the Eleventh Book of the Social Code (SGB XI) and therefore follows a demand-driven understanding of care, which also aligns with public discourse.In order to meet the increasing number of people in need of long term care - mostly caused by demographic change - with needs-based service structures, knowledge and evaluation of several factors are necessary: the prevalence of care dependency as defined by the SGB XI, the different degrees of severity, and the utilisation of long-term care and healthcare services.In this respect, the article presents findings and calculations based on currently available administrative data from German health and long-term care insurance funds and states its limitations. In terms of an actual epidemiological approach to the topic of long-term care, the aim should be broader reporting based on primary surveys.


Asunto(s)
Atención a la Salud , Cuidados a Largo Plazo , Humanos , Alemania/epidemiología , Prevalencia , Instituciones de Salud
3.
Cancer Cell ; 36(6): 630-644.e9, 2019 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-31735627

RESUMEN

The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia.


Asunto(s)
Proteína p300 Asociada a E1A/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proteínas de Unión al ADN/genética , Humanos , Translocación Genética
4.
Cancer Cell ; 36(2): 123-138.e10, 2019 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-31303423

RESUMEN

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.


Asunto(s)
Biomarcadores de Tumor/genética , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 21 , Subunidad beta Común de los Receptores de Citocinas/genética , Síndrome de Down/genética , Factor de Transcripción GATA1/genética , Leucemia Mieloide/genética , Reacción Leucemoide/genética , Mutación , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Síndrome de Down/diagnóstico , Factor de Transcripción GATA1/metabolismo , Regulación Leucémica de la Expresión Génica , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/patología , Reacción Leucemoide/diagnóstico , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Transgénicos , Fenotipo , Transcripción Genética
5.
Cancer Cell ; 34(6): 996-1011.e8, 2018 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-30537516

RESUMEN

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.


Asunto(s)
Biomarcadores de Tumor/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Transcriptoma , Adulto , Biomarcadores de Tumor/metabolismo , Evolución Molecular , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factores de Riesgo , Secuenciación Completa del Genoma/métodos
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