Caractérisation d'une nouvelle translocation des leucémies aiguës lymphoblastiques T t(6;7)(q23;q34)

PARIS-BIUP (751062107) / SudocSudocFranceF

The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL) - the translocation defining a new T-ALL subtype in very young children.

The c-Myb transcription factor is essential for primitive and adult hematopoiesis, including in the T-cell lineage. The c-myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified two types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n=6 cases). Second, a genome wide copy-number analysis by array-CGH identified short somatic duplications which include C-MYB (MYB(dup), n=13 cases out of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared to other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to downregulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median 2.2 years-old) and with a proliferation/mitosis expression signature. By contrast, the MYB(dup) alteration was associated to the previously defined T-ALL subtypes

Assessment of Mendelian and risk factor genes in Alzheimer disease: a prospective nationwide clinical utility study and recommendations for genetic screening

International audiencePurpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92).Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees.Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure